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Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue… (Sasso et al, 2022)

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600
Transient receptor potential melastatin 3 dysfunction in post COVID-19 condition and myalgic encephalomyelitis/chronic fatigue syndrome patients


Abstract

Background
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multisystemic condition associated with post-infectious onset, impaired natural killer (NK) cell cytotoxicity and impaired ion channel function, namely Transient Receptor Potential Melastatin 3 (TRPM3). Long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has resulted in neurocognitive, immunological, gastrointestinal, and cardiovascular manifestations recently recognised as post coronavirus disease 2019 (COVID-19) condition. The symptomatology of ME/CFS overlaps significantly with post COVID-19; therefore, this research aimed to investigate TRPM3 ion channel function in post COVID-19 condition patients.

Methods
Whole-cell patch-clamp technique was used to measure TRPM3 ion channel activity in isolated NK cells of N = 5 ME/CFS patients, N = 5 post COVID-19 patients, and N = 5 healthy controls (HC). The TRPM3 agonist, pregnenolone sulfate (PregS) was used to activate TRPM3 function, while ononetin was used as a TRPM3 antagonist.

Results
As reported in previous research, PregS-induced TRPM3 currents were significantly reduced in ME/CFS patients compared with HC (p = 0.0048). PregS-induced TRPM3 amplitude was significantly reduced in post COVID-19 condition compared with HC (p = 0.0039). Importantly, no significant difference was reported in ME/CFS patients compared with post COVID-19 condition as PregS-induced TRPM3 currents of post COVID-19 condition patients were similar of ME/CFS patients currents (p > 0.9999). Isolated NK cells from post COVID-19 condition and ME/CFS patients were resistant to ononetin and differed significantly with HC (p < 0.0001).

Conclusion
The results of this investigation suggest that post COVID-19 condition patients may have impaired TRPM3 ion channel function and provide further evidence regarding the similarities between post COVID-19 condition and ME/CFS. Impaired TRPM3 channel activity in post COVID-19 condition patients suggest impaired ion mobilisation which may consequently impede cell function resulting in chronic post-infectious symptoms. Further investigation into TRPM3 function may elucidate the pathomechanism, provide a diagnostic and therapeutic target for post COVID-19 condition patients and commonalities with ME/CFS patients.

The study: https://molmed.biomedcentral.com/articles/10.1186/s10020-022-00528-y
 

MonkeyMan

Senior Member
Messages
408
Excellent. I really think Long COVID is our ticket out of this nightmare, and this study is just one example of why. As hard as they've tried to find answers, the woefully under-funded researchers who've worked for years and years on ME/CFS seem absolutely flummoxed. Whereas, with millions upon millions of dollars now being allocated for Long COVID research, and the increasing pressure from the Long COVID community for answers (like their excellent "How Long" campaign), we finally have reason to hope that answers will be forthcoming shortly.
 
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600
Im speculating the problem in mecfs could be general second messenger dysfunction.

Staines and Gradisniks research on problems in these calcium ion channels are pretty convincing to me. Also there is the Petter et al 2022 study which could imply elevated calcium levels in the cells (elevated sodium could reverse the sodium/calcium transporter).

And now there is also the genetic finding mentioned in Dibble et al 2022 where male patients with SNPs in PDE10A are more likely to get mecfs. This enzyme is supposed to break down cAMP and cGMP in the cells so their signalling effects doesnt last forever.

So calcium, cAMP and cGMP are all second messengers and if they dont come and go into the cytosol in timely fashion and in correct amounts the cells are probably going to be a complete mess.
 

Violeta

Senior Member
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3,010
Chapter on TRPM3

Alexander Kushnir, Steven O. Marx, in Cardiac Electrophysiology: From Cell to Bedside (Seventh Edition), 2018

https://www.sciencedirect.com/science/article/abs/pii/B978032344733100002X

All TRP channels are nonselective cation channels exhibiting a <10-fold selectivity for Ca2+ over Na+, with the exceptions of the monovalent cation-selective TRPM4 and TRPM5 and the Ca2+-selective TRPV5 and TRPV6. TRP channels are insensitive to membrane voltage, and instead open in response to a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, phospholipids, and the metabolites of phospholipids (Fig. 2.4D).

Modulators of Transient Receptor Potential Ion Channels


Rajagopal Bakthavatchalam, S. David Kimball, in Annual Reports in Medicinal Chemistry, 2010


Human TRPM3 is a divalent permeable channel that is expressed predominantly in kidney but also in brain, testis, and spinal cord. In TRPM3-expressing HEK293 cells the channel is rapidly and reversibly activated by the neuroactive steroid pregnenolone sulfate (PS), which also activates endogenous TRPM3 channels in insulin-producing β cells. Administration of PS leads to a rapid calcium influx and enhanced insulin secretion from pancreatic β cells and pancreatic islets. To date, no specific TRPM3 antagonist has been reported.

Do you see anything here that would provide a reason for TRPM3 dysfunction in ME/CFS and post COVID?

I am thinking oxidative stress.

I don't know anything about pregnenolone sulfate, but I'll keep looking.
 

Violeta

Senior Member
Messages
3,010
This could be why COVID aggrevates diabetes.

Transient Receptor Potential (TRP) Cation Channels in Diabetes


Koenraad Philippaert, Rudi Vennekens, in TRP Channels As Therapeutic Targets, 2015


TRPM3 channels are also proposed to constitute a regulated Zn2 + entry pathway in pancreatic ß cells [57]. Zinc is important for insulin release as it is packed into cocrystals with insulin in the exocytotic vesicles. The formation of insulin crystals in β cells depends, among others, on the ZnT8 transporter, which contributes to the packaging efficiency of stored insulin [58]. Because Zn2 + ions are coreleased with insulin, pancreatic β cells need to continuously replenish their Zn2 + stores by taking up Zn2 + ions from the extracellular space. Insufficient Zn2 + uptake leads to impaired insulin synthesis and aggravated diabetic symptoms [59].
 
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