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Are ion channels always coupled to receptor proteins??

JohnBoy2000

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Working my way through Rang and Dales Pharmacology - on the chapter about anti-epileptics.

The primary mechanism seems to be, blockade of Sodium or Calcium channels, and I think, positive allosteric modulation of - Phosphorous channels??

Looking at pharmaco-dynamic binding profiles of drugs, receptor subtypes - mainly 5HT - seem to be, G-protein coupled.

But then of course there are ionic channel coupled receptor proteins.

So my question: when anti epileptics like, valproic acid or, whatever; when it's mentioned they blocked ion channels, which inhibit membrane hyperpolarization and thus neurotransmitter release.
Is essentially what they're saying is, the drugs are specific to receptor subtypes which are ion channel coupled??

Such as - I don't know - whatever they may be: glutamatergic or the other primary amino acid receptors.
One or two of the 5HT subtypes, etc.


OR.

Are ion channels just, occurring independently of cellular membrane receptor proteins?
And if so - what normally regulates them?

I know by example, the transporter proteins implicated in SSRI's are based on ionic gradients, which would thusly indirectly function on ion channel transmission.
So - there must be a naturally occurring regulatory mechanism of some kind, right?
 
There are ligand gated channels that change conformation and allow ion flow after ligand binding (see GABA-A or 5-HT3) but there are also ion channels that just flux ions. Sodium channel antagonists can sit in the channel and plug it up.

NMDA channels are a weird example I suppose, you can have antagonists of e.g. the glycine receptor component but also antagonists that sit inside the channel.
 
Okay - so, there are channels that aren't receptor protein based - didn't know that.

The transduction or "cascade" effect of ion channel coupled receptor proteins like GABA-A, 5HT3 or NMDA etc - in comparison to g-protein receptors where the g-protein uncouples and then something something protein phosphorylation via kinase activation etc - that's their cascade process.

Ion channel coupled receptors - their effect is greater than simply modulation of their coupled ion channel, and implications of that - right?

Of course it is but - anyone know the next step following ligand binding?
Also protein phosphorylation?
Obviously not g-protein uncoupling....

In fact - if someone could briefly list that entire process for ion channel coupled receptors, from ligand binding, right through to transcription factor incorporation into the existing genome and thusly modification of genetic expression, the bio and physiological implications of this yielding the AD or whatever, affect.

From what I understand, that is the basis for drug action.

Again - if something can outline their understanding of this process - just to refresh my memory?
 
Okay - so, there are channels that aren't receptor protein based - didn't know that.

The transduction or "cascade" effect of ion channel coupled receptor proteins like GABA-A, 5HT3 or NMDA etc - in comparison to g-protein receptors where the g-protein uncouples and then something something protein phosphorylation via kinase activation etc - that's their cascade process.

Ion channel coupled receptors - their effect is greater than simply modulation of their coupled ion channel, and implications of that - right?

Of course it is but - anyone know the next step following ligand binding?
Also protein phosphorylation?
Obviously not g-protein uncoupling....

In fact - if someone could briefly list that entire process for ion channel coupled receptors, from ligand binding, right through to transcription factor incorporation into the existing genome and thusly modification of genetic expression, the bio and physiological implications of this yielding the AD or whatever, affect.

From what I understand, that is the basis for drug action.

Again - if something can outline their understanding of this process - just to refresh my memory?

Sure can. I taught a course on Neuropharmacology this summer, so it's all pretty fresh. :)

You've got two major types of membrane receptors: GPCRs and ligand-gated ion channels. GPCRs activate different signaling cascades depending upon their coupling. Gs will stimulate the adenylyl cyclase pathway, while Gi/o will inhibit it. There are also Gq receptors that activate the PLC pathway, which can also synergistically interact with other intracellular pathways, but usually increases the activity of the cell.

Then, there are ion channels. These are almost always made up of 5 protein subunits that form a pore, or hole through the middle. Some are always open, like the leaky K+ channels, while others are closed until activated by a neurotransmitter or drug (most of the ones you are familiar with: GABA, serotonin, dopamine, glutamate, etc.). In addition, you've also got voltage gated ion channels. These work much the same as e.g. a classic AMPA receptor, except rather than being activated by a neurochemical binding they are activated by a change in voltage across the membrane. Some drugs produce effects on these as well. The classic example is cocaine, which blocks the voltage gated sodium channels that are highly concentrated along axons. This is why cocaine is a great local anesthetic- by blocking conductance of APs down a nerve fiber, you can block the sensations encoded- like pain.

So yes, ion channels can have a greater effect than GPCRs. By regulating ion influx/efflux they can directly modulate the electrical properties of the cell, and also interact with the other intracellular signaling pathways (which often involve Ca++, an ion, as a messenger).
 
And don't forget connexon channels that form gap-junctions, and cell to cell contact-mediated ephaptic coupling.
 
There are also some ion channels that open in response to mechanical factors, such as TRPV1 (sensitive to heat and capsaicin) and TRPM8 (sensitive to cold and menthol). IUPHAR has a pretty good overview of TRP ion channel families.

I'd also recommend reading their overview of voltage-gated sodium channels, which is a bit dense and hard for me to read but has some good info.
 
Honestly man just get a textbook on psychobiology. It tells you everything a lot more explicitly and cogently. The fact that you don't seem to know what signal proteins (GPCRs) are is telling. You honestly can't learn this online.
 
Honestly man just get a textbook on psychobiology. It tells you everything a lot more explicitly and cogently. The fact that you don't seem to know what signal proteins (GPCRs) are is telling. You honestly can't learn this online.

Can you recommend a title?

You mean, psychobiology books would be more detailed that regular pharmacology books?
 
Can you recommend a title?

You mean, psychobiology books would be more detailed that regular pharmacology books?


Malenka RC, Nestler EJ, Hyman SE (2009). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. ISBN 9780071481274.
You can either buy it, or click this link, and then accept the fact that you might start saying things like "Arrrrr matey."

The third edition (2015 revision) has the ISBN: 9780071827690.
 
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