TRPC6 channels, Serotonin & St. John's Wort for sleep, and maybe for Alzheimer's dementia and autism too.

TRP channels are so neat. A Nobel Prize was deserved for TRP channel research.

An answer was shared by Nattering Naybob regarding how St. John’s Wort may be helping with sleep via modulation of serotonin levels within the brain. It inhibits reuptake, so whatever level of serotonin is present would be used longer. — Thanks!

"St. John’s Wort is a herbal medicinal which modulates serotonin metabolism - how I don’t know." (from this post, Early morning wake-ups - might be low serotonin.)

"St. John’s Wort can inhibit reuptake of serotonin"

Since the ENS produces most of your serotonin, SJW effect on its metabolism is at the neuron.

Hyperforin (in St. John's Wort) apparently inhibits serotonin uptake by elevating intracellular concentrations of sodium (Na) and calcium (Ca).

Activation of TRPC6 by hyperforin leads to an increase in sodium uptake by neurons, resulting in a decrease of the sodium gradient between the neuron and the synaptic cleft. The loss of the gradient decreases reuptake of the monoamine neurotransmitters. Hyperforin also increases the number of [serotonin] 5-HT receptors. (Klemow, et al., 2011)

Blocking the reuptake of serotonin (5-HT) from the synaptic cleft alleviates symptoms of depression by allowing the serotonin to bind to 5-HT receptors and elicit a greater response. (Klemow, et al., 2011) - Nattering Naybob

~~ Let’s learn more about TRPC6 channels….

“TRPC6 is a non-selective cation channel 6 times more permeable to Ca(2+) than to Na(+). Channel homotetramers heterologously expressed have a characteristic doubly rectifying current-voltage relationship and are directly activated by the second messenger diacylglycerol (DAG). TRPC6 proteins are also regulated by specific tyrosine or serine phosphorylation and phosphoinositides.” (Dietrich and Gudermann, 2014)

~~ Brave AI on whether Hyperforin is a phosphoinositide → No, but it can be a compound molecule with a phosphoinositide:

St. John’s Wort (Hypericum perforatum) is a herbal remedy that has been used for centuries to treat various ailments. Hyperforin, a phloroglucinol derivative, is one of the main bioactive components of St. John’s Wort. Research has shown that hyperforin contributes to the pharmacological activities of St. John’s Wort, including its antidepressant effects.

Pharmacological Activities

Hyperforin has been demonstrated to have antidepressant-like activity in various behavioral models of depression. It has also been shown to induce apoptosis (programmed cell death) in human malignant cell lines, making it a potential candidate for cancer treatment.

Phosphoinositide Hyperforin

Phosphoinositides are a class of phospholipids that play important roles in various cellular processes, including signal transduction and membrane trafficking. Hyperforin has been found to interact with phosphoinositides, which may contribute to its pharmacological activities.

Conclusion

In summary, phosphoinositide hyperforin is a bioactive component of St. John’s Wort that has been shown to have antidepressant-like activity and induce apoptosis in human malignant cell lines. Further research is needed to fully understand the mechanisms by which hyperforin interacts with phosphoinositides and to explore its potential therapeutic applications.

Context (Klemow, et al., 2011), (Vacek, et al., 2007), (Zanoli, 2004)

Let’s learn a little more about TRPC6 channels - with the underlying query: Are there any other conditions for which St. John’s Wort might help?

The TRPC6 channels are involved in contraction of smooth muscle, which is the type in the intestinal wall. Excess activity of TRPC6 channels within the lung’s endothelial cells (lining blood vessels) would cause excess fluid and edema to occur after a blood vessel clotting incident “ischaemia–reperfusion oedema formation in the lungs” (?). TRPC6 channels are involved in kidney cells and can be protective of brain cells after a clotting incident occurred in the brain. Functions in blood and immune cells are unclear.

“Given its specific expression pattern, TRPC6 is likely to play a number of physiological roles which are confirmed by the analysis of a Trpc6 ^−/− mouse model. In smooth muscle Na⁺ influx through TRPC6 channels and activation of voltage-gated Ca²⁺ channels by membrane depolarisation is the driving force for contraction. Permeability of pulmonary endothelial cells depends on TRPC6 and induces ischaemia–reperfusion oedema formation in the lungs. TRPC6 was also identified as an essential component of the slit diaphragm architecture of kidney podocytes and plays an important role in the protection of neurons after cerebral ischaemia. Other functions especially in immune and blood cells remain elusive. Recently identified TRPC6 blockers may be helpful for therapeutic approaches in diseases with highly activated TRPC6 channel activity.” (Dietrich and Gudermann, 2014)

St. John’s Wort is an agonist, an activator of the TRPC6 channels rather than being an inhibitor. (Klemow, et al., 2011)

TRPC6 channels are activated by Arachidonic Acid metabolites, (Table 1, Kumar, Goswami, Goswami, 2013) therefore any condition with hyperinflammation is going to lead to excessive TRPC6 channel activation - and maybe lung edema (?). The solution would be to reduce whatever is causing the inflammation and to increase antioxidants, magnesium, and polyphenols to help cope with the oxidative stress. Magnesium would help reduce calcium entry into cells where it can cause endocannabinoid release from membranes which then leads to arachidonic acid accumulation as the endocannabinoids are broken down into eicosanoids.

Which conditions are likely to involve over expression of TRPC6 channels?

TRPC6 channels are over-expressed in several chronic illnesses, including:

• Kidney diseases: TRPC6 channels are extensively present throughout the kidney, and their over-activation has been linked to kidney pathologies. They contribute to the progression of acquired glomerular diseases, including primary and secondary focal segmental glomerulosclerosis (FSGS), glomerulosclerosis during autoimmune glomerulonephritis, and possibly in type-1 diabetes. (Dryer, Roshanravan and Kim, 2019)

• Pulmonary diseases: TRPC6 channels are expressed in human airway smooth muscle cells (HASMCs) and play a crucial role in the development of various lung diseases, including cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, lung oedema, and lung fibrosis. (Saqib, et al., 2023)

  • *Aside: Cystic fibrosis (CF) is a condition with a gene difference that interferes with production of endocannabinoids due to not being able to attach the fatty acid. People with CF would chronically be low in endocannabinoids and likely would benefit from using an external source, (*like medical marijuana or CBD drops).

  • Since they can’t make endocannabinoids well, then dietary arachidonic acid might be adding to an overactivation of the TRPC6 channels, and cause worsening lung edema. Boiled chicken/brothy chicken preparations can be a dietary source of a lot of free arachidonic acid.

  • *A patient with Cystic fibrosis was a major case study project during my dietetic internship and in my career I had a family with two children with CF so I am somewhat familiar with this genetic condition. I later learned that my own gene differences cause a similar lack of endocannabinoid production except I can’t make the phospholipid end of the molecule instead. My health problems are less severe than someone with CF has to cope with.

• Neurological diseases: TRPC6 deficiency or increased activity due to gain-of-function mutations has been associated with neurological diseases. (Saqib, et al., 2023)

“TRPC6 is abundantly expressed in various regions of the Central Nervous System (CNS) [16, 37]. As a regulator of Ca²⁺ influx, TRPC6 is involved in the survival of neurons, synaptic plasticity, nerve growth cone guidance, spine morphology changes, and the regulation of neurite length [38,39,40,41,42]. Dysregulation of TRPC6 activity may trigger a series of downstream signalling events leading to many neurobiological disorders (Fig. 3). TRPC6 along with TRPC3 play an important role in brain-derived neurotrophic factor (BDNF)-induced axon guidance and neuron survival [38]. Consistently, one study reported an increased expression of TRPC6 in hippocampus during the postnatal development [40].” (Saqib, et al., 2023) *See Figure 3.

Figure 3: TRPC6 in the nervous system. Increased activity: 1) Improves survival of neurons during cerebral ischemic injury. 2) Regulates spine morphology. 3) Reduces accumulation of beta-amyloid plaques. Deficiency was associated with: 1) Neurodegenerative diseases (Alzheimer’s disease) 2) Autism spectrum disorders. (Saqib, et al., 2023)

These findings suggest that TRPC6 channels may play a significant role in the pathogenesis of various chronic illnesses, and their dysregulation may contribute to the progression of these diseases.

Context: en.wikipedia.org, TRPC6 - Wikipedia; (Saqib, et al., 2023); (Dryer, Roshanravan and Kim, 2019)

TAKE HOME POINT: These findings also suggest that St. John’s Wort might help prevent or treat Alzheimer’s dementia and autism (Saqib, et al., 2023) by promoting expression and activity of TRPC6 channels. (Klemow, et al., 2011)

Disclaimer: This information is being provided for educational purposes within the guidelines of Fair Use and is not intended to provide individual health care guidance.

Reference List

(Dietrich and Gudermann, 2014) Dietrich A, Gudermann T. TRPC6: physiological function and pathophysiological relevance. Handb Exp Pharmacol. 2014;222:157-88. doi: 10.1007/978-3-642-54215-2_7. PMID: 24756706. https://link.springer.com/chapter/10.1007/978-3-642-54215-2_7

(Dryer, Roshanravan and Kim, 2019) Dryer SE, Roshanravan H, Kim EY. TRPC channels: Regulation, dysregulation and contributions to chronic kidney disease. Biochim Biophys Acta Mol Basis Dis. 2019 Jun 1;1865(6):1041-1066. doi: 10.1016/j.bbadis.2019.04.001. Epub 2019 Apr 4. PMID: 30953689. https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(19)30112-7

(Klemow, et al., 2011) Klemow KM, Bartlow A, Crawford J, et al. ‘Medical Attributes of St. John’s Wort (Hypericum perforatum)’, In: Benzie IFF, Wachtel-Galor S, editors. Herbal Medicine: Biomolecular and Clinical Aspects. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis; 2011. Chapter 11. Available from: https://www.ncbi.nlm.nih.gov/books/NBK92750/

(Kumar, Goswami, Goswami, 2013) Kumar, A., & Goswami, L., & Goswami, C., 2013. ‘Importance of TRP channels in pain: Implications for stress’. Frontiers in bioscience (Scholar edition). S5. 19-38. Available at: https://www.researchgate.net/publication/234019431_Importance_of_TRP_channels_in_pain_Implications_for_stress

(Saqib, et al., 2023) Saqib, U., Munjuluri, S., Sarkar, S. et al. Transient Receptor Potential Canonical 6 (TRPC6) Channel in the Pathogenesis of Diseases: A Jack of Many Trades. Inflammation 46, 1144–1160 (2023). https://doi.org/10.1007/s10753-023-01808-3 https://link.springer.com/article/10.1007/s10753-023-01808-3

(Vacek, et al., 2007) Vacek J, Klejdus B, Kubán V. Hypericin a hyperforin: biologicky aktivní komponenty trezalky teckované (Hypericum perforatum). Jejich izolace, analýza a studium fyziologických úcinků [Hypericin and hyperforin: bioactive components of St. John's Wort (Hypericum perforatum). Their isolation, analysis and study of physiological effect]. Ceska Slov Farm. 2007 Apr;56(2):62-6. Czech. PMID: 17619301. https://pubmed.ncbi.nlm.nih.gov/17619301/

(Zanoli, 2004) Zanoli P. Role of hyperforin in the pharmacological activities of St. John's Wort. CNS Drug Rev. 2004 Fall;10(3):203-18. doi: 10.1111/j.1527-3458.2004.tb00022.x. PMID: 15492771; PMCID: PMC6741737. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741737/