Ion Channels

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OverviewModelIon ChannelsMemory | C-Fibers & Touch | Mysteries

Sodium, calcium and potassium channels are involved in almost every process within the body, including muscle contractions, cardiac function, and sensory experience. Impairment of ion channels is known as “channelopathy”, and can be either congenital or acquired eg. from an autoimmune disease.

Various medications such as calcium channel blockers are clearly designed to act on these channels, but many others like antidepressants and anticonvulsants also act on a variety of ion channels.

All 5-HT (serotonin) receptors, except one, belong to the family of G protein-coupled receptors (GPCR). The exception is 5-HT3 (S3), which is a direct ion channel.

The 5-HT3 receptor has close links to the family of TRP channels which seem to be the most important receptors mediating the experiences of touch or numbness, pain, heat, tingling and other sensations, all of which seem abnormal in withdrawal and in Post-SSRI Sexual Dysfunction (PSSD).

For anyone who knows a physiologist or pharmacologist – and for the rest of us there is Google – we need reviews of:

  1. Sodium channels – both fast and slow sodium currents.
  2. Potassium channels.
  3. Calcium channels – L, P, N, R & T types and their link to serotonin and dopamine receptors.
  4. TRP A, M and V Channels.
  5. The on-off effects of treatments on withdrawal and PSSD.

Above all we need feedback on anything that makes a difference and what it makes a difference to. It’s likely there are many herbs and related compounds out there that help, and if so it is possible that some of these help because they have effects on TRP channels or sodium channels, or other elements for which we don’t at present have conventional drugs.

There may also be “machines” or devices that might help, such as those that deliver Low Power Laser Irradiation (LPLI) or Frequency Specific Microcurrent (FSM) stimulation.

Calcium channels

For anyone interested in withdrawal related issues, calcium channels and calcium-activated potassium channels are important for a number of reasons.

Some of the most commonly used drugs in medicine are calcium channel blockers – verapamil, diltiazem and nifedipine. One key question is – do people on calcium channel blockers get protracted withdrawal or PSSD when they take an SSRI?

Is there a difference between verapamil and other blockers in this respect?

Verapamil has been used to manage tardive dyskinesia and withdrawal from antipsychotics which opens up the possibility that they may also be of help in the protracted syndromes linked to antidepressant and benzodiazepine withdrawal.

It appears that among the older antipsychotics some such as haloperidol and trifluoperazine (Stelazine) were more likely to be linked to withdrawal and tardive dyskinesia than others such as pimozide, and the difference lies in their effects on calcium channels.

Anandamide which is thought to be one of the body’s own activators of the cannabinoid receptor also acts to block calcium channels – see table.

The biphosphonate drugs that are used to manage osteoporosis have an effect on calcium distribution and produce possibly more side effects than any other drug group in medicine, including many of the features of protracted withdrawal syndrome.

Ca
Channel
LocationActivatorInhibitorBlocker
1.1Muscle
Brain
Spinal cord
BAYK8644
FPL64176
Isradipine
Devapamil
Diltiazem
Nifedipine
Nitrendipine
Cadmium
Diltiazem
Verapamil
Calciseptin
1.2Heart
Brain
Muscle
Prostate
Bladder
Gut
Adrenals
Spinal cord
BAYK8644
FPL64176
Isradipine
Devapamil
Diltiazem
Nifedipine
Nitrendipine
Nimodipine
Verapamil
Palladium
Cadmium
Mibefradil
Diltiazem
Verapamil
Calciseptin
1.3Brain
Spinal cord
Adrenals
Retina
BAYK8644
Isradipine
Azidopine
Nifedipine
Nitrendipine
Nimodipine
Amlodipine
Cadmium
Verapamil
1.4Lymph tissue
Retina
Spinal cord
BAYK8644Verapamil
Nifedipine
Diltiazem
2.1Brain
Spinal cord
Auditory
Kidney
Sperm
Agatoxin
Kurtoxin
Grammotoxin
Mibefradil
Nickel
Cadmium
Conotoxin
2.2Brain
Spinal cord
Auditory
Sperm
Kurtoxin
Grammotoxin
Conotoxin
Cilnidipine
Palladium
2.3Brain
Spinal cord
Auditory
Kidney
Sperm
Mibefradil
Nickel
Palladium
Cadmium
Nickel
3.1Brain
Spinal cord
Ovaries
KurtoxinPimozide
Mibefradil
Nickel
3.2Brain
Kidney
Liver
Heart
Lung
Muscle
Pancreas
KurtoxinPimozide
Mibefradil
Anandamide
Nickel
3.3BrainKurtoxinPimozide
Mibefradil
Anandamide
Nickel

Potassium channels

There is an urban myth – eat 6 bananas and you die. Bananas are a rich source of potassium, and many people in a compromised physical condition with low potassium are encouraged to eat bananas as the best possible way to get it. But, too much potassium can also kill, hence the idea that a bunch of bananas can be fatal. It’s not true. You would have to eat vast amounts of bananas to be at risk.

As the table below indicates though, there are all kinds of lethal poisons that act through potassium channels such as tubocurarine. But many psychotropic drugs linked to withdrawal, cardiac effects and peripheral neuropathy (ethanol) also act through various potassium channels.

In terms of cardiac function, the famous QT interval problem linked to antidepressants, antipsychotics and drugs such as fluoroquinolone and macrolide antibiotics is linked to a voltage-gated potassium channel called hERG channels. These hERG channels vary in all of us – so that some of us are born with long QT intervals – and for us drugs that make the problem worse can be very tricky. The risk becomes even greater when multiple drugs that affect QT interval are prescribed, often without adequate consideration of these risks by the prescriber or informed consent by the taker.

See Sudden cardiac death & The Reverse Dodo Verdict [1].

It seems to be the case that almost all drugs that cause protracted withdrawal syndromes also cause QT interval problems – so potassium channels warrant close attention.

Potassium channels play a major role in corporal smooth muscle tone/contractility, which is necessary for erectile function [2]. See The Sexiest Channels Alive: The Role of Ion Channels in Penile Erection.

Ca Activated
K Channel
LocationActivatorInhibitorBlocker
K 1BrainFlindokalner
Estradiol
Slotoxin
Paxilline
K 2.1Brain
Heart
Kidney
Gut
CalciumBicuculline
Tubocurarine
Tetraethylammonium
K 2.2Brain
Heart
Spinal cord
Bladder
Liver
Prostate
Riluzole
Calcium
Chlorzoxazone
Bicuculline
Tubocurarine
Tetraethylammonium
K 2.3Brain
Gut
Muscles
Uterus
Riluzole
Calcium
Dequalinium
Tubocurarine
Tetraethylammonium
K 3.1Placenta
Lung
Gut
Lymph nodes
Bone marrow
Chlorzoxazone
Riluzole
Clotrimazole
Nitrendipine
Senicapoc
Na Linked
K 1.1Kidney
Brain
Testis
Sodium
Chloride
Niclosamide
Loxapine
Calcium
Bepridil
Quinidine
Tetraethylammonium
K 1.2Brain
Muscles
Kidney
Testis
Lung
Liver
Sodium
Chloride
Niflumic acid
ATP
Phorbol
Quinidine
Tetraethylammonium
Barium
K 5.1Testis
Sperm
Quinidine
Tetraethylammonium
Inwardly Rectifying
K Channel
Brain
Heart
Muscle
Testis
Kidney
ATP
Potassium
Arachidonic acid
Ethanol
Nicorandil
Minoxidil
Fluoxetine
Clozapine
Haloperidol
Thioridazine
Magnesium
Rubidium
Spermidine
Spermine
Clomipramine
Desipramine
Imipramine
Amitriptyline
Two-P
K Channels
Arachidonic acid
Riluzole
Halothane
Anandamide
Voltage Gated
K Channels
Linoleic acid
Zinc
Flupirtine
Capsaicin
Diltiazem
Halothane
Quinine

Sodium channels

There are a lot of reasons to implicate sodium channels in the disturbances linked to protracted withdrawal and PSSD.

A flow of sodium ions is the first component of the electrical currents that underpin all of our behavior. All antidepressants, but in particular those with effects on the serotonin system, affect sodium currents.

Lithium, one of the first psychotropic drugs that worked, comes with a significant withdrawal syndrome. At one point in the 1960s, a lot of people were convinced that lithium worked by exchanging with body sodium and that the essential problem underpinning manic-depressive illness involved an imbalance of sodium. These views have fallen out of favor – through neglect more than disproof.

Antidepressants, especially those active on the serotonin system, can cause blood sodium levels to fall low enough to kill.

Some of the treatments promoted as helpful for withdrawal such as lamotrigine are primarily sodium channel blockers – see table below.

Local anaesthetics work by blocking the flow of sodium ions and thereby preventing nerve signals from being transmitted. Pancrazio et al (1998) noted that the effects of tricyclic antidepressants (TCAs) on sodium ion current in bovine cells, was similar to a local anaesthetic [3].

Antidepressants and anticonvulsants are commonly prescribed as a treatment for neuropathic pain. It is believed their efficacy for pain may be due to their known ability for ion channel blockade [4], and in particular their effect on sodium channels [5].

The genital numbness that can be experienced in PSSD can be mimicked by rubbing lidocaine into the genitals – and lidocaine, as the table shows is a sodium channel blocker. Lidocaine used to be used as a treatment for premature ejaculation before SSRIs. The challenge therefore seems to be to do the opposite to lidocaine – to stimulate sodium flow – to activate the channels, or to compensate in some other way.

The problem is that sodium is so fundamental to life, that most agents that act on sodium channels turn out to be toxins or otherwise deadly.

But it seems there are several compounds out there in nature that might do useful things. The trick is to find ones that do the right thing to the right extent. Many of the anticonvulsants such as valproic acid and lamotrigine act on sodium, proving that it is possible to produce treatments that act on sodium channels.

Or it might be that a device would be a safer option – low power laser irradiation (LPLI) has been shown to reverse some of the genital numbness found in PSSD [6]. Someone with an electrical background may have insights on what is needed.

Na
Channel
LocationActivatorInhibitorBlocker
1Brain
Spinal cord
Batrachotoxin
Veratridine
ATX-11
Cangitoxin-II
Bc-III
AFT-II
Tetrodotoxin
Conotoxin
Saxitoxin
2Brainβ-Scorpion toxin (PA)
Batrachotoxin
Aconitine (PA)
Veratridine (PA)
α-Scorpion toxin
Huwentoxin IV
Protoxin II
ATX-11
Bc-III
AFT-II
δ-Hexatoxin
Tetrodotoxin
Conotoxin
Saxitoxin
Etidocaine
Lidocaine
Phenytoin
Lacosamide
Lamotrigine
3Brain
Spinal cord
Heart
Batrachotoxin
Veratridine
ATX-11
Bc-III
AFT-II
Tetrodotoxin
Lacosamide
Saxitoxin
4MuscleGrayanotoxin
Batrachotoxin
Veratridine
β-Scorpion toxin
ATX-11
Bc-III
AFT-II
Tetrodotoxin
Conotoxin
Saxitoxin
Mexiletine
Lidocaine
5HeartAconitine
Batrachotoxin
Veratridine
α-Scorpion toxin
Jingzhaotoxin
Protoxin
ATX-11
Bc-III
AFT-II
Tetrodotoxin
Conotoxin
Saxitoxin
Lidocaine
Amiodarone
Quinidine
6Peripheral nervesβ-Scorpion toxin
Batrachotoxin
Veratridine
ATX-11
Bc-III
AFT-II
Tetrodotoxin
Saxitoxin
7Peripheral nervesBatrachotoxin
Veratridine
N-Me-amino-pyrimidino-NE9XEN907
Tetrodotoxin
Saxitoxin
Lacosamide
Lidocaine
Cadmium
8Peripheral nervesBatrachotoxin
Veratridine
Lacosamide
Tetrodotoxin
Lidocaine
9PeripheralTetrodotoxin

Transient receptor potential (TRP) channels

TRP Channels

Most medics coming to this page will know no more than someone who has never had anything to do with biology or medicine. TRP channels are the new kids on the block and even those who are the experts know relatively little. If you want to bamboozle your doctor, this is the language to speak.

We desperately need anyone reading this to begin to look further into the issues. If you locate any good and easy to read resources about TRP channels, please pass them on. If you locate someone who has hands on knowledge point her/him this way.

TRP channels are a subset of the ion channels that crucially are involved in the processing of sensory information ie. vision, hearing, smell, taste, temperature, and various touch sensations including temperature and pain. A genetic mutation of TRPM1 has been linked to congenital stationary night blindness [7,8]. TRP channels can be expected to be involved in sensory neuropathies and so they are of central importance to many of the features linked to protracted withdrawal syndromes.

As the image above suggests, many herbs or health food supplements and metals have effects on various TRP channels where orthodox medicine might once have denied that these compounds had any specific effects.

These are not just weak effects. Looking through the tables below makes it clear that some of the most lethal poisons known to man also act on these receptors. There is nothing wishy-washy, all in the mind about these effects. The task is to see if we can locate the problems linked to withdrawal and PSSD in some of these channels, or sodium or other channels – or more importantly if we can act on one of these channels in a way that alleviates problems.

TRP A & C ChannelsLocationActivatorInhibitorBlocker
TRP A1Lung
Gut
Brain
Heart
Skin
Nerves
Apomorphine
THC
Nicotine
Menthol
Isoflurane
Niflumic acid
Gentamicin
Menthol
Resolvin
Gadolinium
Ruthenium red
Amiloride
TRP C1Brain
Viscera
Testes
Gadolinium
Lanthanum
TRP C2Testes
Sperm
Heart
Brain
DOG
OAG
SAG
TRP C3Brain
Spinal cord
Testes
Retina
Muscle
Gut
OAGGadolinium
Lanthanum
Nickel
TRP C4Heart
Brain
Pancreas
Kidney
Gut
Lanthanum
Englerin
Niflumic acid
TRP C5Brain
Testis
Uterus
Bladder
Gadolinium
Lead
Rosiglitazone
Calcium
Phosphatidylcholine
Progesterone
Lactone
Chlorpromazine
TRP C6EverythingArachidonic acid
Phosphatidylcholine
Hyperforin
Flufenamate
Gadolinium
Lanthanum
Amiloride
TRP C7Kidney
Pituitary
Gut
Brain
DOG
AOG
Amiloride
Lanthanum
TRP M ChannelsLocationActivatorInhibitorBlocker
M 1Skin
Retina
PregnenoloneZinc
M 2Brain
Spinal cord
Viscera
Blood cells
Eye
NAD
Arachidonic acid
ADP - IC
Calcium - IC
Flufenamic acid
Clotrimazole
Econazole
Miconazole
Zn2+
M 3Brain
Spinal cord
Eye
Ovaries
Testes
Viscera
Sphinganine
Sphingosine
Nifedipine
Epipregnanolone
Pregnenolone
Mg2+
Gd3+
La3+
Rosiglitazone
Extracelluar Na+
Mefenamic acid
Troglitazone
Pioglitazone
M 4Viscera
Prostate
Testes
Brain
Muscle
Adipose
Bone
Decavanadate
PIP2
Calcium IC
Clotrimazole
Adenosine diphosphate
Flufenamic acid
ATP
AMP-PNP
ATP
9-Phenanthrol
Spermine
Adenosine
M 5Viscera
Pituitary
Calcium ICFlufenamic acid
Spermine IC
M 6Viscera
Testes
Magnesium ICRuthenium red
Calcium
Magnesium
M 7Pituitary
Bone
Adipose
PIP2
ATP IC
La3+
Spermine
Sphinosine
Fingolimod
Waixenicin A
Carvacrol
Nafamostat
Mg2+
M 8Prostate
Breast
Testes
Bladder
Spinal cord
Icilin
Menthol
Eucalyptol
Linalool
Frescolat
Capsazepine
5-Benzyloxytryptamine
Linoleic acid
Anandamide
Tetrahydrocannabinol
La3+
Cannabidiol
NADA
ML 1Brain
Bone
Thymus
Blood cells
Phosphatidylinositol biphosphate
ML 2VisceraPhosphatidylinositol biphosphate
ML 3Brain
Viscera
Phosphatidylinositol biphosphateGadolinium
TRP P & V ChannelsLocationActivatorInhibitorBlocker
P 1Testes
Ovary
Viscera
Lung
Calcium ICCadmium
Nickel
P 2Testes
Retina
Muscle
Brain
Calcium
Citric acid
Malic acid
Gd3+
La3+
Phenamil
Benzamil
Amiloride
Flufenamate
P 3Testes
V 1Brain
Spinal cord
Testes
Viscera
Capsaicin
Resiniferatoxin
Olvanil
Anandamide
Piperine
Camphor
Capsazepine
Ruthenium red
Allicin
NADA
V2Skin
Blood cells
Retina
Diphenylboronic anhydride
Lysophosphatidylcholine
IGF 1
Neuropeptide head activator
Cannabidiol
Tetrahydrocannabinol
Probenecid
Tetraethylammonium
Fampridine
TRIM
Citral
Ruthenium red
Amiloride
La3+
V 3Brain
Spinal cord
Skin
Testes
Tongue
Hair
Pituitary
Vanillin
Eugenol
Cinnamaldehyde
Camphor
Carvacrol
Thymol
Citral
Cannabidiol
Carveol
Borneol
(-)-menthol
Ruthenium red
Isopentenyl pyrophosphate
Aspirin-triggered resolvin D1
Diphenyltetrahydrofuran
V 4Airways
Viscera
Skin
Eicosatrienoic acid
Bisandrographolide
Citric acid
Ruthenium red
Gd3+
La3+
V 5Prostate
Testes
Brain
Viscera
Ruthenium red
Mg2+
Econazole
Miconazole
V 6Ruthenium red
Mg2+
Cd2+
La3+

Thermosensors

Some TRP channels act as thermosensors. Free nerve endings in the epidermal layer of the skin contain a sensor on their outer membrane (a single protein) which are temperature sensitive, each responding at different temperature thresholds:

  • TRPV1 – heat (activated >109°F) … also activated by chilli / capsaicin
  • TRPV2 – extreme heat
  • TRPV3 – gentle warmth … also activated by spices (cinnamon, cloves, etc.)
  • TRPV4 – gentle warmth
  • TRPM8 – cooling (activated <78°F) … also activated by menthol
  • TRPA1 – “heat” sensation produced by wasabi, horseradish, etc.

TRP Thermosensors

These protein molecules respond by opening an ion channel, a pore that lets positive ions flow inside, thereby causing the sensory neuron to fire electrical spikes.

Thresholds for hot (TRPV1) and cold (TRPM8) detection are unique to each species depending on core body temperature.

Drugs that block TRPV1 or activate TRPM8 can lead to hyperthermia.

Cooling (‘mint’/ menthol) and heat (‘chilli’ / capsaicin) both feel the same because they activate the same brain regions dedicated to the sensation of cooling/heat.

It is likely that there are more heat detectors within the skin that have yet to be discovered – perhaps some that are unrelated to TRP channels.

Note: This information on thermosensors is sourced from the book Touch – The Science of Hand, Heart, and Mind by David J. Linden (2015).

Further reading

The information in all of the above tables is sourced from the IUPHAR/BPS Guide to Pharmacology, where you can find more information about ion channels:

A comprehensive guide to TRP channels can also be found in the book Mammalian Transient Receptor Potential (TRP) Cation Channels – Volume 2. Editors: Bernd Nilius and Veit Flockerzi.

References

  1. Healy D, Howe G, Mangin D, Le Noury J. Sudden cardiac death & The Reverse Dodo Verdict. Int J Risk Saf Med. 2014;26(2):71-9.
  2. Christ GJ. Gap junctions and ion channels: relevance to erectile dysfunction. Int J Impot Res. 2000 Oct;12 Suppl 4:S15-25.
  3. Pancrazio JJ, Kamatchi GL, Roscoe AK, Lynch C 3rd. Inhibition of neuronal Na+ channels by antidepressant drugs. J Pharmacol Exp Ther. 1998 Jan;284(1):208-14.
  4. Sindrup SH1, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol. 2005 Jun;96(6):399-409.
  5. Thériault O, Poulin H, Beaulieu JM, Chahine M. Differential modulation of Nav1.7 and Nav1.8 channels by antidepressant drugs. Eur J Pharmacol. 2015 Oct 5;764:395-403. doi:10.1016/j.ejphar.2015.06.053.
  6. Waldinger MD, van Coevorden RS, Schweitzer DH, Georgiadis J. Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) responds to low-power laser irradiation: a case study and hypothesis about the role of transient receptor potential (TRP) ion channels. Eur J Pharmacol. 2015 Apr 15;753:263-8. doi:10.1016/j.ejphar.2014.11.031. PMID 25483212.
  7. Pan Z, Capó-Aponte JE, Reinach PS (2012). Transient Receptor Potential (TRP) Channels in the Eye. Advances in Ophthalmology ISBN 978-953-51-0248-9
  8. Ribelayga C. Vertebrate Vision: TRP Channels in the Spotlight. Curr Biol 2010 Mar 23; 20(6): R278–R280