I went about looking at various ways of activating CREB so I can get some good LTP. CaMPKII looked promising. You can activate it with calcium, calmodulin, ATP, and then permanently using phospho-Thr-286 which sounds fun and dangerous.
So what I don't see a who lot of talk about is Calmodulin. Would more of it produce better LTP? Does it reduce calcium in a good way, binding it to be useful? Is it short lived or does it kick around a while? Would the downstream effects of CREB use up cAMP if it is over-produced (like in ADD)?
I mean... never heard of it until I looked up CaMPKII and there's barely any chatter. Let's start it up! So...
The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission, controlling the length and brevity of dopaminergic signaling. DAT is also the primary target of psychostimulant drugs such as cocaine and amphetamines. Conversely, methylphenidate and amphetamine are both used clinically in the treatment of attention-deficithyperactivitydisorder and narcolepsy. The action of amphetamines, which induce transport reversal, relies primarily on the ionic composition of the intra- and extracellular milieus. Recent findings suggest that DAT interacting proteins may also play a significant role in the modulation of reverse dopamine transport. The pharmacological inhibition of the serine/threonine kinase αCaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP(+)) efflux. More importantly, αCaMKII has also been shown to bind DAT in vitro and is therefore believed to be an important player within the DAT interactome. Herein, we show that αCaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack αCaMKII or which express a permanently self-inhibited αCaMKII (αCaMKII(T305D)), exhibit significantly reduced amphetamine-triggered DAT-mediated MPP(+) efflux. Additionally, we investigated mice that mimic a neurogenetic disease known as Angelman syndrome. These mice possess reduced αCaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the αCaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome.
Equilibrative nucleoside transporters (ENTs) facilitate the flux of nucleosides, such as adenosine, and nucleoside analog (NA) drugs across cell membranes. A correlation between adenosine flux and calcium-dependent signaling has been previously reported; however, the mechanistic basis of these observations is not known. Here we report the identification of the calcium signaling transducer calmodulin (CaM) as an ENT1-interacting protein, via a conserved classic 1-5-10 motif in ENT1. Calcium-dependent human ENT1-CaM protein interactions were confirmed in human cell lines (HEK293, RT4, U-87 MG) using biochemical assays (HEK293) and the functional assays (HEK293, RT4), which confirmed modified nucleoside uptake that occurred in the presence of pharmacological manipulations of calcium levels and CaM function. Nucleoside and NA drug uptake was significantly decreased (∼12% and ∼39%, respectively) by chelating calcium (EGTA, 50 μM; BAPTA-AM, 25 μM), whereas increasingintracellular calcium (thapsigargin, 1.5 μM) led to increased nucleoside uptake (∼26%). Activation of N-methyl-d-aspartate (NMDA) receptors (in U-87 MG) by glutamate (1 mM) and glycine (100 μM) significantly increased nucleoside uptake (∼38%) except in the presence of the NMDA receptor antagonist, MK-801 (50 μM), or CaM antagonist, W7 (50 μM). These data support the existence of a previously unidentified novel receptor-dependent regulatory mechanism, whereby intracellular calcium modulates nucleoside and NA drug uptake via CaM-dependent interaction of ENT1. These findings suggest that ENT1 is regulated via receptor-dependent calcium-linked pathways resulting in an alteration of purine flux, which may modulate purinergic signaling and influence NA drug efficacy.
CAMTAs: calmodulin-binding transcription activators from plants to human.
Recently, a novel family of calmodulin-binding transcription activators (CAMTAs) was reported in various eukaryotes. All CAMTAs share a similar domain organization, with a novel type of sequence-specific DNA-binding domain (designated CG-1). This domain could bind DNA directly and activate transcription, or interact with other transcription factors, not through DNA binding, thus acting as a co-activator of transcription. Investigations of CAMTAs in various organisms imply a broad range of functions from sensory mechanisms to embryo development and growth control, highlighted by the apparent involvement of mammalian CAMTA2 in cardiac growth, and of CAMTA1 in tumor suppression and memory performance.
Little is known about the genes and proteins involved in the process of human memory. To identify genetic factors related to human episodic memory performance, we conducted an ultra-high-density genome-wide screen at > 500 000 single nucleotide polymorphisms (SNPs) in a sample of normal young adults stratified for performance on an episodic recall memory test. Analysis of this data identified SNPs within the calmodulin-binding transcription activator 1 (CAMTA1) gene that were significantly associated with memory performance. A follow up study, focused on the CAMTA1 locus in an independent cohort consisting of cognitively normal young adults, singled out SNP rs4908449 with a P-value of 0.0002 as the most significant associated SNP in the region. These validated genetic findings were further supported by the identification of CAMTA1 transcript enrichment in memory-related human brain regions and through a functional magnetic resonance imaging experiment on individuals matched for memory performance that identified CAMTA1 allele-specific upregulation of medial temporal lobe brain activity in those individuals harboring the 'at-risk' allele for poorer memory performance. The CAMTA1 locus encodes a purported transcription factor that interfaces with the calcium-calmodulin system of the cell to alter gene expression patterns. Our validated genomic and functional biological findings described herein suggest a role for CAMTA1 in human episodic memory.
Just kidding. Actually it didn't clear it up at all. I need an adult.
I think what it is saying is that those with a specific CAMTA1 allele with poorer long term memory performance have to think back harder? Or their brain goes crazier in that region, more likely to burn out? Again, not really getting their conclusion from poorer-memory performance to some part of brain activity known for associative memory processing... I would think that it is a good thing, but here it is clearly implied as a poor memory quality for episodic memory.
Maybe I'm just reading it wrong. There were no cups at the coffee machine, and I'm running on fumes before dinner.
Alright, here are the less confusing articles I don't need help understanding, since Wiki did a great job summarizing their importance regarding CaMKII activation by Calmodulin:
"Long-term potentiation (LTP) requires a depolarization of GABAergic neurons (Neurons that use GABA as a neurotransmitter) in the hippocampus."
Long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus
The plasticity of GABAergic synapses was investigated in neonatal rat hippocampal slices obtained between postnatal days 3 and 6 using intracellular recording techniques. Ionotropic glutamate receptor antagonists were present throughout the experiments to isolate GABAA receptor-mediated postsynaptic potentials (GABAA PSPs) or currents (GABAA PSCs).
Repetitive depolarizing pulses (20 pulses, 0·5 s duration, at 0·1 Hz, each pulse generating 4-6 action potentials) induced a long-term potentiation in the slope and amplitude of the evoked GABAA PSPs and GABAA PSCs.
Long-term potentiation was prevented by intracellular injection of the calcium chelator BAPTA (50 mM), or when the voltage-dependent calcium channels blockers Ni2+ (50 μM) and nimodipine (10 μM) were bath applied.
Repetitive depolarizing pulses induced a persistent (over 1 h) increase in the frequency of spontaneous GABAA PSCs.
Repetitive depolarizing pulses induced a long-lasting increase in the frequency of miniature GABAAPSCs, without altering their amplitude or decay-time constant.
It is concluded that the postsynaptic activation of voltage-dependent calcium channels leads to a long-term potentiation of GABAergic synaptic transmission in neonatal rat hippocampus. This form of plasticity is expressed as an increase in the probability of GABA release or in the number of functional synapses, rather than as an upregulation of postsynaptic GABAA receptor numbers or conductance at functional synapses.
The activity-dependent plasticity of glutamatergic synapses has been described extensively (Nicoll & Malenka, 1995) and is believed to play a crucial role in learning and memory processes. Because activity-dependent plasticity of GABAergic synaptic transmission could also modify the input-output relationship of the neurones, study of this form of plasticity is essential.
Long-term changes in synaptic efficacy may be expressed as presynaptic alterations in neurotransmitter release or as postsynaptic modifications in the sensitivity to released neurotransmitter. One approach to address postsynaptic modifications is to measure the amplitude of responses induced by application of neurotransmitter agonist. This method does not, however, provide compelling evidence since exogenously applied agonist may activate extrasynaptic receptors that could be under different modulatory control than the synaptic ones (Boxall & Marty, 1997). A more direct approach is to measure the amplitude and frequency of spontaneous synaptic currents that occur independently of action potential firing. A change in the amplitude of these events, referred to as miniature postsynaptic currents, is usually considered to reflect a postsynaptic modification, while a change in their frequency is considered to reflect a presynaptic modification. This method, however, requires that a significant number of synapses impinging on the recorded neurone are affected to make postsynaptic modifications detectable.
In a previous study we reported that early in development GABAergic synaptic transmission expresses a calcium-dependent bidirectional plasticity in the neonatal rat hippocampus (McLean et al. 1996). Thus, concomitant activation of GABAA and NMDA receptors during a high-frequency stimulation leads to long-term depression of GABAergic synaptic transmission, while activation of only GABAA receptors leads to a long-term potentiation of GABAergic synaptic transmission. The long-term potentiation of GABAergic synaptic transmission requires a membrane depolarization, provided by the activation of GABAA receptors, and a rise in intracellular calcium concentration, probably resulting from an influx of calcium through voltage-dependent calcium channels. In the present study, we show that direct activation of postsynaptic voltage-dependent calcium channels in the absence of synaptic stimulation results in a long-term potentiation (LTP) of evoked and spontaneous GABAA receptor-mediated postsynaptic potentials or currents in neonatal rat CA3 pyramidal neurones (LTPGABAA). The conditioning stimulus also leads to a long-lasting increase in the frequency, but not amplitude, of spontaneous and miniature GABAA receptor-mediated postsynaptic currents. Therefore, LTPGABAA is expressed as an increase in the probability of GABA release or in the number of functional GABAergic synapses, but not as an upregulation of postsynaptic GABAA receptors at previously functional GABAergic synapses.
"Calmodulin Kinase II (CaM-K II) plays a crucial role in achieving LTP. It contributes to the phosphorylation of an AMPA receptor which increases the sensitivity of AMPA receptors. Furthermore, research shows that inhibiting CaM-K II interferes with LTP."
Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism.
Ca(2+)-sensitive kinases are thought to play a role in long-term potentiation (LTP). To test the involvement of Ca2+/calmodulin-dependent kinase II (CaM-K II), truncated, constitutively active form of this kinase was directly injected into CA1 hippocampal pyramidal cells. Inclusion of CaM-K II in the recording pipette resulted in a gradual increase in the size of excitatory postsynaptic currents (EPSCs). No change in evoked responses occurred when the pipette contained heat-inactivated kinase. The effects of CaM-K II mimicked several features of LTP in that it caused a decreased incidence of synaptic failures, an increase in the size of spontaneous EPSCs, and an increase in the amplitude of responses to iontophoretically applied alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate. To determine whether the CaM-K II-induced enhancement and LTP share a common mechanism, occlusion experiments were carried out. The enhancing action of CaM-K II was greatly diminished by prior induction of LTP. In addition, following the increase in synaptic strength by CaM-K II, tetanic stimulation failed to evoke LTP. These findings indicate that CaM-K II alone is sufficient to augment synaptic strength and that this enhancement shares the same underlying mechanism as the enhancement observed with LTP.
Those studies really don't have to do with increasing Calmodulin, per se...
And here's the thing. There are different calmodulins, the most studied of which is the Calmodulin 1 protein. This is encoded by the CALM1 gene. And here is the Pubmed data on this one, showing it has many interactions with different transmitters and systems associated with cognition if anyone cares to dig a little deeper:
Basically chronic morphine causes an accumulation in the thalamus, probably the brain's way of being not-so-sleepy, more of a tolerance effect. Thalamus has to do with awakeness...
Same thing happens in the stratium with dopamine antagonists...
Again, it sounds like a counter-response, seeing as how that is the reward center to the brain. Another mechanism in tolerance.
I wonder if there is anything that is healthy? Lol, these are weird... it's almost as if these are the things that we want the most. When you're pumped up with morphine, you want to just find something to do to fight the lethargy. When you're apathetic from anti-psychotics, all you want to do is find something to do to perk you up.
I wonder if increasing calmodulin is correlated with conscience/semi-conscience effort? If we mechanism behind will power, that would be epic.
Apocalmodulin Itself Promotes Ion Channel Opening and Ca2+Regulation
Highlights
•ApoCaM binding to CaV1.3 channels boosts channel open probability up to 7-fold
•RNA editing and alternative splicing of Cav1.3 tunes apoCaM affinity
•One apoCaM boosts both opening and subsequent Ca2+-dependent channel inactivation
•ApoCaM modulation of open probability is conserved between CaV and NaVchannels
Summary
The Ca2+-free form of calmodulin (apoCaM) often appears inert, modulating target molecules only upon conversion to its Ca2+-bound form. This schema has appeared to govern voltage-gated Ca2+ channels, where apoCaM has been considered a dormant Ca2+ sensor, associated with channels but awaiting the binding of Ca2+ions before inhibiting channel opening to provide vital feedback inhibition. Using single-molecule measurements of channels and chemical dimerization to elevate apoCaM, we find that apoCaM binding on its own markedly upregulates opening, rivaling the strongest forms of modulation. Upon Ca2+ binding to this CaM, inhibition may simply reverse the initial upregulation. As RNA-edited and -spliced channel variants show different affinities for apoCaM, the apoCaM-dependent control mechanisms may underlie the functional diversity of these variants and explain an elongation of neuronal action potentials by apoCaM. More broadly, voltage-gated Na channels adopt this same modulatory principle. ApoCaM thus imparts potent and pervasive ion-channel regulation.
So... it sounds like the apocalyptic sounding version of calmodulin self-regulates itself, so that it is more active when empty vs. when with calcium. That's cool, since the studies where it was upregulated by drugs were in parts of the brain that probably needed the most calcium.
The dopamine transporter (DAT) is a crucial regulator of dopaminergic neurotransmission, controlling the length and brevity of dopaminergic signaling. DAT is also the primary target of psychostimulant drugs such as cocaine and amphetamines. Conversely, methylphenidate and amphetamine are both used clinically in the treatment of attention-deficithyperactivitydisorder and narcolepsy. The action of amphetamines, which induce transport reversal, relies primarily on the ionic composition of the intra- and extracellular milieus. Recent findings suggest that DAT interacting proteins may also play a significant role in the modulation of reverse dopamine transport. The pharmacological inhibition of the serine/threonine kinase αCaMKII attenuates amphetamine-triggered DAT-mediated 1-methyl-4-phenylpyridinium (MPP(+)) efflux. More importantly, αCaMKII has also been shown to bind DAT in vitro and is therefore believed to be an important player within the DAT interactome. Herein, we show that αCaMKII co-immunoprecipitates with DAT in mouse striatal synaptosomes. Mice, which lack αCaMKII or which express a permanently self-inhibited αCaMKII (αCaMKII(T305D)), exhibit significantly reduced amphetamine-triggered DAT-mediated MPP(+) efflux. Additionally, we investigated mice that mimic a neurogenetic disease known as Angelman syndrome. These mice possess reduced αCaMKII activity. Angelman syndrome mice demonstrated an impaired DAT efflux function, which was comparable with that of the αCaMKII mutant mice, indicating that DAT-mediated dopaminergic signaling is affected in Angelman syndrome.
CaMKII = a natural DRI? That's pretty cool stuff. Seems like it is really important for stimulant responsiveness!
Looks like ADHDer's are more likely to be horny (D2 upregulation), which is pretty much in line with the trend of ADHD in society. Sorry, that was a side note. The cool thing was that methylphenidate increased CaMPKII in the mPFC but not in the hippocampus, meaning great for spatial memory but no good for long term memory.
Aberrant CaMKII activity in the medial prefrontal cortex is associated with cognitive dysfunction in ADHDmodel rats.
Attention-deficit/hyperactivitydisorder (ADHD) is a heterogeneous neurobehavioral disorder accompanied by cognitive and learning deficits, which is prevalent among boys. Juvenile male stroke-prone spontaneously hypertensive rats (SHRSP) exhibit ADHD-like behaviors including cognitive deficits and represent one animal model of ADHD. Here, we define a mechanism underlying cognitive dysfunction observed in SHRSP. Acute methylphenidate (MPH: 1mg/kg, p.o.) administration to SHRSP significantly improved not only inattention in a Y-maze task but also cognitive dysfunction in a novel object recognition test. Interestingly, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) activity, which is essential for memory and learning acquisition, was excessively elevated in the medial prefrontal cortex (mPFC) but not in the hippocampal CA1 region of SHRSP compared with Wistar-Kyoto (WKY) rats. We also confirmed that elevated CaMKII autophosphorylation in the mPFC causes increased phosphorylation of the CaMKII substrate α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid-type glutamate receptor subunit 1 (GluR1) (Ser-831). Ca(2+)-dependent phosphorylation levels of factors such as extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) were unchanged in the SHRSP mPFC. Also, protein levels of the dopamine D2 receptor (D2R) but not the dopamine D1 receptor (D1R) were increased in the SHRSP mPFC. Acute MPH (1mg/kg, p.o.) administration attenuated aberrant CaMKII activity and increased GluR1 phosphorylation observed in SHRSP. Taken together, we propose that cognitive impairment in SHRSP is associated with aberrant CaMKII activity in the mPFC.
Antiamnesic effect of B. monniera on L-NNA induced amnesia involves calmodulin.
Amnesia may result from ageing, chronic drug abuse or head injury and there are limited therapeutic strategies to such conditions. We have shown that Bacopa monniera, a memory enhancing drug can reverse both diazepam and scopolamine induced amnesia in mice. In order to understand the downstream effects of B. monniera, this study was designed to investigate how B. monniera antagonizes MK801, an NMDA receptor antagonist and N(omega)-Nitro-L-arginine (L-NNA), a nitric oxide synthase inhibitor. We compared the degree of reversal B. monniera imparts on MK801 and L-NNA induced anterograde amnesia in experimental mice. Our data revealed that L-NNA induced anterograde amnesia was significantly reversed by B. monniera, however, it did not attenuate the MK 801 induced anterograde amnesia. B. monniera significantly increased calmodulin (CaM) and pCREB/CREB levels when the whole brain lysates of B. monniera pretreated amnesic mice were compared with those of L-NNA treated mice. We conclude that antiamnesic effect B. monniera on L-NNA induced amnesia may be mediated by NO pathyway involving CaM, which is required for LTP sustenance. These studies evoke interest in their future development as potential antiamnesic drugs.
Looks like Bacopa reverses NO Synthase inhibition, thereby upping calmodulin (CAM).
I'm wondering why we haven't heard more anecdotal evidence of Bacopa acting synergistically with stimulants?
Actually--
'Delta Gamma', on 15 Nov 2010 - 9:51 PM, said:
Unfortunately it only says it contains 100mg of Bacomind per pill, which given the recommended two pills per day comes to 200mg per day.
Though some further research on my part suggests that if there are any fatigue inducing properties that the Canadian ginseng and ginkgo extracts (5% ginsenosides 100mg a pill, and 24% flavoglycosides/ 6% terpene lactones respectively) may help mask them. If I recall correctly ginkgo had some sort of antagonistic effect on GABA receptors, and ginseng has some sort of vague fatigue reducing properties. It doesn't make me tired per say, but I find that it when I relax I feel much more tired than I would otherwise until I get back to work.
I'm more wondering about the potentiation of stimulants it provides, it makes me a little uneasy about possible drug interactions. Though with my previous experiences with ginkgo and ginseng (at similar dosages and extract strengths), there is definitely something that Bacomind either does independently or through some sort of synergy.
I've always been under the impression that Bacopa can be mildly sedating, and it's one of the few herbs I haven't tried; so, I'll have to see how it plays with my modafinil prescription.
I've always been under the impression that Bacopa can be mildly sedating, and it's one of the few herbs I haven't tried; so, I'll have to see how it plays with my modafinil prescription.
I actually haven't tried any brands other than Bacopin, but it definitely made the next day drag when taking at night at any more than 100mg. Some days more than others, which made it really difficult to sustain. I'm pretty sensitive to serotonergic sedatives, so maybe that was it (even straight 5-HTP does the same thing). You could always go with a full spectrum extract or dried leave powder instead of a standardized one. Read the reviews!
Androgen and Estrogen raise calmodulin levels in gold fish eyes. Not really close to practical, but it could explain why there are people who are high responders to things like pregnenolone.
On the other end, the neurprotective effects of glucocorticoids like corticosterone seem to be completely inhibited by a lack of calmodulin (and ATP):
Glucocorticoids reduce intracellular calcium concentration and protects neurons against glutamate toxicity.
Glucocorticoids are steroid hormones which act through the glucocorticoid receptor. They regulate a wide variety of biological processes. Twoglucocorticoids, the naturally occurring corticosterone and chemically produced dexamethasone, have been used to investigate the effect ofglucocorticoids on Ca(2+)-signalling in cortical co-cultures of neurons and astrocytes. Dexamethasone and to a lesser degree corticosterone both induced a decrease in cytosolic Ca(2+) concentration in neurons and astrocytes. The effect of both compounds can be blocked by inhibition of the plasmamembrane ATPase, calmodulin and by application of a glucocorticoid receptor antagonist, while inhibition of NMDA receptors or the endoplasmic reticulum calcium pump had no effect. Glucocorticoid treatment further protects against detrimental calcium signalling and cell death by modulating the delayed calcium deregulation in response to glutamate toxicity. At the concentrations used dexamethasone and corticosterone did not show cell toxicity of their own. Thus, these results indicate that dexamethasone and corticosterone might be used for protection of the cells from calcium overload.
Which makes sense considering this study regarding the actions of piracetam analogues:
Involvement of a steroidal component in the mechanism of action of piracetam-like nootropics.
Since adrenalectomy abolishes the memory-enhancing effects of piracetam and its derivatives, oxiracetam, aniracetam and pramiracetam, the question arises whether endogenous steroids play a role in their mechanism of action. We show that inhibition of steroid biosynthesis by aminoglutethimide and blockade of the aldosterone receptors by epoxymexrenone completely suppress the memory-improving effects of the nootropics. These results indicate that steroids, or, more precisely, activities mediated by the aldosterone receptors, might be involved in the mechanism of action of this class of nootropics. Blockade of aldosterone receptors, however, does not block the effects of cholinomimetics on memory, indicating the involvement of another mechanism of action.
Calmodulin is a widely distributed, highly active, calcium-binding protein that influences a number of important biological events. Accordingly, agents that inhibit the activity of calmodulin should have profound pharmacological effects. Within the past few years, a number of compounds have been identified that inhibit calmodulin. The most potent of these described so far include certain antipsychotic drugs, smooth muscle relaxants, alpha-adrenergic blocking agents and neuropeptides. Studies of the physicochemical and structural properties of a variety of calmodulin inhibitors have shown that there are ionic and hydrophobic interactions between the drug and calmodulin. From the limited studies conducted so far, we conclude that, for a compound to inhibit calmodulin, it should carry a positive charge at physiological pH, presumably to interact with negative charges on the highly acidic calmodulin, and have hydrophobic groups, presumably to interact with lipophilic regions on calmodulin. But these two factors are not the only ones that are involved in inhibiting calmodulin, for many highly charged and highly hydrophobic agents have relatively little effect on calmodulin activity. The structural relationships between these ionic and hydrophobic regions and other, as yet identified, factors are also important. Many of the biochemical actions of the phenothiazine antipsychotic agents can be explained by the common mechanism of their binding to, and inhibiting, calmodulin. The question of whether these biochemical actions can explain their pharmacological and clinical effects is still unclear. The fundamental role calmodulin plays in biology suggests that this calcium binding protein may provide a new site for the pharmacological manipulation of biological activity. The calmodulin inhibitors described thus far hardly scratch the surface of this fertile area of research.
Calmodulin is a widely distributed, highly active, calcium-binding protein that influences a number of important biological events. Accordingly, agents that inhibit the activity of calmodulin should have profound pharmacological effects. Within the past few years, a number of compounds have been identified that inhibit calmodulin. The most potent of these described so far include certain antipsychotic drugs, smooth muscle relaxants, alpha-adrenergic blocking agents and neuropeptides. Studies of the physicochemical and structural properties of a variety of calmodulin inhibitors have shown that there are ionic and hydrophobic interactions between the drug and calmodulin. From the limited studies conducted so far, we conclude that, for a compound to inhibit calmodulin, it should carry a positive charge at physiological pH, presumably to interact with negative charges on the highly acidic calmodulin, and have hydrophobic groups, presumably to interact with lipophilic regions on calmodulin. But these two factors are not the only ones that are involved in inhibiting calmodulin, for many highly charged and highly hydrophobic agents have relatively little effect on calmodulin activity. The structural relationships between these ionic and hydrophobic regions and other, as yet identified, factors are also important. Many of the biochemical actions of the phenothiazine antipsychotic agents can be explained by the common mechanism of their binding to, and inhibiting, calmodulin. The question of whether these biochemical actions can explain their pharmacological and clinical effects is still unclear. The fundamental role calmodulin plays in biology suggests that this calcium binding protein may provide a new site for the pharmacological manipulation of biological activity. The calmodulin inhibitors described thus far hardly scratch the surface of this fertile area of research.
Awesome, specifically, it mentions the phenothiazine derivitives, of which methylene blue is closely related. My chronic experience with that compound has been disappointing, increasing my CDD/ADHD-PI symptoms over several days when initially was seemingly effective in certain areas of cognition. Since stopping it, I feel a lot better.
Basically, a plant (https://en.wikipedia...storta_vivipara) has some effect on NO Synthase, presumably by the Ca+/Calmodulin pathway. It's used in peripheral healing, so that makes sense. It's an astringent and styptic. It's toxic with chronic use if eaten raw, due to it's oxalic acid content, so I would say that it's probably a bad idea to eat it every day. Cooking reduces oxalic acid, so I suppose it might be okay to add it as a vegetable/spice in a cooked entre.
Hmm... I thought increasing led to NO Synthase led to increased Calmodulin, but it almost says it's the other way around?
Yes, Methylene Blue has been a weird one in my experience. Loved it at first, but it's so darn hard to separate the placebo effect. I mean, those lovely blue swirls...lol...it just LOOKS like it should make you feel better. Plus, I was taking it while doing a ridiculous amount of aerobic exercise, training for a marathon, and I DID immediately notice an increase in stamina (guessing mitochondria...but really who knows); however, the increase in stamina was NOTHING compared to C60/OO...another supplement/RC with a huge potential for placebo effect-- I mean who doesn't think ingesting anything NANO is going to do something amazing, if it doesn't give you cancer.
I'd like to try Methylene Blue again but this time I'm going with either pharma grade methylene Blue crystals, or Azure B, the biologically active metabolite of M blue. Before I was using the fish tank M Blue, which made me feel a little gangsta. Like I was going to pick up fish antibiotics to heal my gunshot wound instead of going to the hospital...Plus, it's a little tough not to be drinking fish tank disinfectant and not think, "What the hell am I doing?" Then again, it's tough not to take any RC mailed from China and not think the same thing!
Really enjoying this thread and waiting for some of the less "bathroom" scientists that I am to weigh in.
A theory about that phenomenon (that has been mentioned by others, too): Direct AMPA receptor potentiation leads to a reduction of CAMKII activity (the most important AMPA receptor potentiating signalling protein and essential for memory formation). Somehow this new functioning of brain cells is preserved even after cessation of the nootropic. It would be interesting to see whether indirect AMPA receptor potentiators (CAMKII activators) like nobiletin or tianeptine are able to reverse this.
In the case, that You was a Cocaine addict, I would try to use a CaMKII inhibitor.
Cocaine activates either directly or indirectly (so as a downstream target) PKG and coincidentally D2 and/or D3 receptors (if I´m not mistaken)
This in turn activates CaMKII and this then Delta FosB (ΔFosB). Heres the interresting part:
ΔFosB increases CaMKII mRna, and thats how a self-reinforcing/stabilizing loop develops. Guess I´ve read it here: http://www.ncbi.nlm....pubmed/23467346
ΔFosB stabilizes Your addiction memory and either increases or decreases dopamine release ( I´ve forgotten it)
I´ve read somewhere that Scutellaria baicalensis or one of its single compounds do inhibit CaMKII but I cant find it anymore.. thanks to google
Anyway Gastrodin and Catalpol "should" inhibit CaMKII as well: http://www.ncbi.nlm....pubmed/23550774 http://www.ncbi.nlm....pubmed/24619207
A theory about that phenomenon (that has been mentioned by others, too): Direct AMPA receptor potentiation leads to a reduction of CAMKII activity (the most important AMPA receptor potentiating signalling protein and essential for memory formation). Somehow this new functioning of brain cells is preserved even after cessation of the nootropic. It would be interesting to see whether indirect AMPA receptor potentiators (CAMKII activators) like nobiletin or tianeptine are able to reverse this.
In the case, that You was a Cocaine addict, I would try to use a CaMKII inhibitor.
Cocaine activates either directly or indirectly (so as a downstream target) PKG and coincidentally D2 and/or D3 receptors (if I´m not mistaken)
This in turn activates CaMKII and this then Delta FosB (ΔFosB). Heres the interresting part:
ΔFosB increases CaMKII mRna, and thats how a self-reinforcing/stabilizing loop develops. Guess I´ve read it here: http://www.ncbi.nlm....pubmed/23467346
ΔFosB stabilizes Your addiction memory and either increases or decreases dopamine release ( I´ve forgotten it)
I´ve read somewhere that Scutellaria baicalensis or one of its single compounds do inhibit CaMKII but I cant find it anymore.. thanks to google
Anyway Gastrodin and Catalpol "should" inhibit CaMKII as well: http://www.ncbi.nlm....pubmed/23550774 http://www.ncbi.nlm....pubmed/24619207
So let me put the disclaimer out there...
Although CAMKII activity is good, it is also problematic to a certain degree as well. There has to be balance:
Take for example the above mentioned study. CAMKII-alpha (the most notable of the CAMKII variants so far that I've come across) is "normalized" and leads to a bettering of symptoms in a PD model of mice using levodopa.
However, the study that references this, states that levodopa also can cause diskenesia, but inhibiting CAMKII-alpha signalling on D2 neurons removes those side effects in chronically treated mice. Although I'm not sure it also doesn't remove some of the main effects...
It seems as though there is some shady calcium signalling going on with CAMKII to blame (doesn't say which variant, but I assume they are talking about CaMKII-alpha). Apparently, CaMKII is also responsible for apoptosis during LPS response of PC12 (rare tumors) cells. I can't see why that's a bad thing... but apparently, the scientists think that catalpol is a good experimental medicine for healthier cells, too... or at least, that's what it implies without actually saying it. They want to say it, but can't, so they stick in there "in PC12" cells, repeatedly. That's my take anyway.
LPS is big molecule hanging off bacteria that illicit an immune response... but also kill PC12 cells. In healthy dendrites, LPS primes the pumps for T-Cell activation:
Anyway, my point is that CaMKII may be part of apoptosis when phospohylized. What I'm suggesting is an increase through cadmodulin, which seems to be a lesser stimulant to CaMKII(-alpha) and almost seems to have a balancing effect.
IIRC I read that DeltaFosbeta is responsible for L-Dopa dyskinesias and that D1 receptor activation elicts dyskinesias:
Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg).
Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease.
I agree, CamkII is imptorant for phisiological functions but I dont know for what exactly.
It would be very helpful if someone knows why or whether to avoid CaMKII inhibition at all costs
..Because CaMKII is ubiquitous and required for many basal neuronal and behavioral functions, direct use of CaMKII inhibitors has been avoided as an addiction treatment...
Behavioral and structural responses to chronic cocaine require a feedforward loop involving ΔFosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell.
CaMKII is certainly required for a number of cognitive processes, but yes, agreed it is even involved in addiction pathways. That doesn't make it bad or good. In fact, I'd say it just makes it essential.
Back to my original idea of increasing calmodulin...
CaMKII is phosphorylized and becomes "permanently" activated. This involves ATP. When this happens, the only way to break it down is via antigens in your body, that I am aware. Reading over what I wrote in the first paragraph, it doesn't make it very clear that phospho-Thr-286 is the site at which ATP permanently activates on the CaMKII protein so that it no longer requires calcium or calmodulin to function. If you look up "phospho-Thr-286" in a search engine, you'll see the sale of antibodies that attack activated CaMKII proteins. Here is a good example:
Here you will see an explanation of its reactivity with other proteins and an explanation of how this peptide is thought to work at dephosphorylizing CaMKII. It appears that phospohrylization is actually reversible, but not automatically like it is will Ca+/Calmodulin.
Do you get what I'm trying to say here? Calmodulin is a way of not only regulating calcium reactivity (its main purpose) but also to gently activate CaMKII in a way that is helpful, not harmful. Consider this article:
To give you an example of what I mean, consider malignant or cancerous cells. They suck up nutrients and survive in normal conditions even throughout their stages of radical growth. They are susceptible to non-endogenous alkaloids and other small molecules, but they thrive in normal conditions. Part of this has to do with their signalling to the the rest of the body to send more resources for their growth. Calcium is a fine example of this. Cancer patients have high calcium levels due to their calcium in the bones getting leeched out to feed the cancer. Cancer cannot survive if it got overloaded with calcium - it's mitochondria would explode and induce apoptosis. So what does it do? It starts making crazy amounts of Calmodulin to protect it's cellular activity and bring things down into a zone where they can run free to destroy your life.
So, now that I've muddied the waters by saying that cancer cells use calmodulin as their calcium elixir, you might think that it is a bad thing. It is not. Similar to the telomerase discussion, it would be like throwing matchsticks on a fire. Even if there is a signalling pathway that involves calmodulin to cause hypercalcemia, there could potentially be the case of "matchsticks on the fire". Consider that calmodulin disablement is a method to reduce "calcium cell proliferation" and therefore a mechanism to kill cancer:
Then you have to consider the inverse correlation of age with calmodulin ( https://www.research...om_Aged_Animals ) and also bone density. Calmodulin should actually stabilize calcium levels so that your bones don't need to give off more calcium. That's my theory, if there are any takers? (Got stuff to do now.)
As my parting gift for the day, I found this video: [See minute 8:14] Which helps you understand the Calmodulin structure. The full video series explains the CaMKII structure with nice little diagrams that are easy to understand.
IIRC I read that DeltaFosbeta is responsible for L-Dopa dyskinesias and that D1 receptor activation elicts dyskinesias:
Topiramate and amantadine exhibited differential antidyskinetic effects on dyskinesia elicited by the dopamine D1 receptor agonist SKF 38393 (2 mg/kg).
Synergistic antidyskinetic effects of topiramate and amantadine in animal models of Parkinson's disease.
I agree, CamkII is imptorant for phisiological functions but I dont know for what exactly.
It would be very helpful if someone knows why or whether to avoid CaMKII inhibition at all costs
..Because CaMKII is ubiquitous and required for many basal neuronal and behavioral functions, direct use of CaMKII inhibitors has been avoided as an addiction treatment...
Behavioral and structural responses to chronic cocaine require a feedforward loop involving ΔFosB and calcium/calmodulin-dependent protein kinase II in the nucleus accumbens shell.
The herb in that last study is not a friendly one to be taking for everyday effects for the everyday person. It increases male hormonal activity causing things like hair loss, for instance.
It might maybe not be good as a nootropic, altough it has some dopamine increasing effects.
but decrasing CaMKII as well as inhibiting Parp-1, which is linked to Sidekick-1 may be good for Cocaine addiction
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