Overview | Model | Ion Channels | Memory | 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:
- Sodium channels – both fast and slow sodium currents.
- Potassium channels.
- Calcium channels – L, P, N, R & T types and their link to serotonin and dopamine receptors.
- TRP A, M and V Channels.
- 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 | Location | Activator | Inhibitor | Blocker |
|---|---|---|---|---|
| 1.1 | Muscle Brain Spinal cord | BAYK8644 FPL64176 | Isradipine Devapamil Diltiazem Nifedipine Nitrendipine | Cadmium Diltiazem Verapamil Calciseptin |
| 1.2 | Heart Brain Muscle Prostate Bladder Gut Adrenals Spinal cord | BAYK8644 FPL64176 | Isradipine Devapamil Diltiazem Nifedipine Nitrendipine Nimodipine Verapamil | Palladium Cadmium Mibefradil Diltiazem Verapamil Calciseptin |
| 1.3 | Brain Spinal cord Adrenals Retina | BAYK8644 | Isradipine Azidopine Nifedipine Nitrendipine Nimodipine Amlodipine | Cadmium Verapamil |
| 1.4 | Lymph tissue Retina Spinal cord | BAYK8644 | Verapamil Nifedipine Diltiazem | |
| 2.1 | Brain Spinal cord Auditory Kidney Sperm | Agatoxin Kurtoxin Grammotoxin Mibefradil | Nickel Cadmium Conotoxin | |
| 2.2 | Brain Spinal cord Auditory Sperm | Kurtoxin Grammotoxin | Conotoxin Cilnidipine Palladium | |
| 2.3 | Brain Spinal cord Auditory Kidney Sperm | Mibefradil Nickel | Palladium Cadmium Nickel | |
| 3.1 | Brain Spinal cord Ovaries | Kurtoxin | Pimozide Mibefradil Nickel | |
| 3.2 | Brain Kidney Liver Heart Lung Muscle Pancreas | Kurtoxin | Pimozide Mibefradil Anandamide Nickel | |
| 3.3 | Brain | Kurtoxin | Pimozide 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 | Location | Activator | Inhibitor | Blocker |
|---|---|---|---|---|
| K 1 | Brain | Flindokalner Estradiol | Slotoxin Paxilline | |
| K 2.1 | Brain Heart Kidney Gut | Calcium | Bicuculline Tubocurarine Tetraethylammonium | |
| K 2.2 | Brain Heart Spinal cord Bladder Liver Prostate | Riluzole Calcium Chlorzoxazone | Bicuculline Tubocurarine Tetraethylammonium | |
| K 2.3 | Brain Gut Muscles Uterus | Riluzole Calcium | Dequalinium Tubocurarine Tetraethylammonium | |
| K 3.1 | Placenta Lung Gut Lymph nodes Bone marrow | Chlorzoxazone Riluzole | Clotrimazole Nitrendipine Senicapoc | |
| Na Linked | ||||
| K 1.1 | Kidney Brain Testis | Sodium Chloride Niclosamide Loxapine | Calcium Bepridil | Quinidine Tetraethylammonium |
| K 1.2 | Brain Muscles Kidney Testis Lung Liver | Sodium Chloride Niflumic acid | ATP Phorbol | Quinidine Tetraethylammonium Barium |
| K 5.1 | Testis 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 | Location | Activator | Inhibitor | Blocker |
|---|---|---|---|---|
| 1 | Brain Spinal cord | Batrachotoxin Veratridine | ATX-11 Cangitoxin-II Bc-III AFT-II | Tetrodotoxin Conotoxin Saxitoxin |
| 2 | Brain | β-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 |
| 3 | Brain Spinal cord Heart | Batrachotoxin Veratridine | ATX-11 Bc-III AFT-II | Tetrodotoxin Lacosamide Saxitoxin |
| 4 | Muscle | Grayanotoxin Batrachotoxin Veratridine β-Scorpion toxin | ATX-11 Bc-III AFT-II | Tetrodotoxin Conotoxin Saxitoxin Mexiletine Lidocaine |
| 5 | Heart | Aconitine Batrachotoxin Veratridine | α-Scorpion toxin Jingzhaotoxin Protoxin ATX-11 Bc-III AFT-II | Tetrodotoxin Conotoxin Saxitoxin Lidocaine Amiodarone Quinidine |
| 6 | Peripheral nerves | β-Scorpion toxin Batrachotoxin Veratridine | ATX-11 Bc-III AFT-II | Tetrodotoxin Saxitoxin |
| 7 | Peripheral nerves | Batrachotoxin Veratridine | N-Me-amino-pyrimidino-NE9 | XEN907 Tetrodotoxin Saxitoxin Lacosamide Lidocaine Cadmium |
| 8 | Peripheral nerves | Batrachotoxin Veratridine | Lacosamide Tetrodotoxin Lidocaine | |
| 9 | Peripheral | Tetrodotoxin |
Transient receptor potential (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 Channels | Location | Activator | Inhibitor | Blocker |
|---|---|---|---|---|
| TRP A1 | Lung Gut Brain Heart Skin Nerves | Apomorphine THC Nicotine Menthol Isoflurane Niflumic acid | Gentamicin Menthol Resolvin | Gadolinium Ruthenium red Amiloride |
| TRP C1 | Brain Viscera Testes | Gadolinium Lanthanum | ||
| TRP C2 | Testes Sperm Heart Brain | DOG OAG SAG | ||
| TRP C3 | Brain Spinal cord Testes Retina Muscle Gut | OAG | Gadolinium Lanthanum Nickel | |
| TRP C4 | Heart Brain Pancreas Kidney Gut | Lanthanum Englerin | Niflumic acid | |
| TRP C5 | Brain Testis Uterus Bladder | Gadolinium Lead Rosiglitazone Calcium Phosphatidylcholine | Progesterone Lactone Chlorpromazine | |
| TRP C6 | Everything | Arachidonic acid Phosphatidylcholine Hyperforin Flufenamate | Gadolinium Lanthanum Amiloride | |
| TRP C7 | Kidney Pituitary Gut Brain | DOG AOG | Amiloride Lanthanum |
| TRP M Channels | Location | Activator | Inhibitor | Blocker |
|---|---|---|---|---|
| M 1 | Skin Retina | Pregnenolone | Zinc | |
| M 2 | Brain Spinal cord Viscera Blood cells Eye | NAD Arachidonic acid ADP – IC Calcium – IC | Flufenamic acid Clotrimazole Econazole Miconazole Zn2+ | |
| M 3 | Brain Spinal cord Eye Ovaries Testes Viscera | Sphinganine Sphingosine Nifedipine Epipregnanolone Pregnenolone | Mg2+ Gd3+ La3+ Rosiglitazone Extracelluar Na+ Mefenamic acid Troglitazone Pioglitazone | |
| M 4 | Viscera Prostate Testes Brain Muscle Adipose Bone | Decavanadate PIP2 Calcium IC | Clotrimazole Adenosine diphosphate Flufenamic acid ATP AMP-PNP | ATP 9-Phenanthrol Spermine Adenosine |
| M 5 | Viscera Pituitary | Calcium IC | Flufenamic acid Spermine IC | |
| M 6 | Viscera Testes | Magnesium IC | Ruthenium red Calcium Magnesium | |
| M 7 | Pituitary Bone Adipose | PIP2 ATP IC | La3+ Spermine Sphinosine Fingolimod Waixenicin A Carvacrol Nafamostat Mg2+ | |
| M 8 | Prostate Breast Testes Bladder Spinal cord | Icilin Menthol Eucalyptol Linalool Frescolat | Capsazepine 5-Benzyloxytryptamine Linoleic acid Anandamide Tetrahydrocannabinol La3+ Cannabidiol NADA | |
| ML 1 | Brain Bone Thymus Blood cells | Phosphatidylinositol biphosphate | ||
| ML 2 | Viscera | Phosphatidylinositol biphosphate | ||
| ML 3 | Brain Viscera | Phosphatidylinositol biphosphate | Gadolinium |
| TRP P & V Channels | Location | Activator | Inhibitor | Blocker |
|---|---|---|---|---|
| P 1 | Testes Ovary Viscera Lung | Calcium IC | Cadmium Nickel | |
| P 2 | Testes Retina Muscle Brain | Calcium Citric acid Malic acid | Gd3+ La3+ Phenamil Benzamil Amiloride Flufenamate | |
| P 3 | Testes | |||
| V 1 | Brain Spinal cord Testes Viscera | Capsaicin Resiniferatoxin Olvanil Anandamide Piperine Camphor | Capsazepine Ruthenium red Allicin NADA | |
| V 2 | Skin Blood cells Retina | Diphenylboronic anhydride Lysophosphatidylcholine IGF 1 Neuropeptide head activator Cannabidiol Tetrahydrocannabinol Probenecid | Tetraethylammonium Fampridine TRIM Citral Ruthenium red Amiloride La3+ | |
| V 3 | Brain 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 4 | Airways Viscera Skin | Eicosatrienoic acid Bisandrographolide Citric acid | Ruthenium red Gd3+ La3+ | |
| V 5 | Prostate Testes Brain Viscera | Ruthenium red Mg2+ Econazole Miconazole | ||
| V 6 | Ruthenium 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.
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:
- Voltage-gated calcium channels
- Potassium channels
- Voltage-gated sodium channels
- Transient Receptor Potential (TRP) 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
- 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.
- Christ GJ. Gap junctions and ion channels: relevance to erectile dysfunction. Int J Impot Res. 2000 Oct;12 Suppl 4:S15-25.
- 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.
- 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.
- 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.
- 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.
- 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
- Ribelayga C. Vertebrate Vision: TRP Channels in the Spotlight. Curr Biol 2010 Mar 23; 20(6): R278–R280