One other clue I have since 2011. I have an epigenetic gene (methylation) "phospholipase a2 (Gene PLA2R1)"
Are you suggesting that you have a polymorphism of this gene and that it could affect the clearance of phospholipase A2 and thus affecting its normal enzymatic cleavage of fatty acids that cause arachiodonic release.
Anandamide - Wikipedia
Anandamide (
ANA), also known as
N-arachidonoylethanolamine (
AEA), is a
fatty acid neurotransmitter.
Anandamide is derived from the non-oxidative metabolism of arachidonic acid, an essential omega-6 fatty acid. It is synthesized from
N-arachidonoyl phosphatidylethanolamine by multiple pathways.
[5] It is degraded primarily by the
fatty acid amide hydrolase (FAAH) enzyme, which converts anandamide into
ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.
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This would seemingly cause an issue with cannabinoid regulation involved in calcium ion channel regulation. This would in turn affect the local immune system to the phospholipase A2 receptors on neurons likely having some affect over the stress response as a result. The affect of a polymorphism doing this could make someone susceptible to HPA activation over normal levels causing a hightened response to input to the HPA axis via stimuli from the outside world and physical processes that activate the HPA to illicit action in some way like the cortisol wake response.
Once an immune issue comes and dysregulates further an already dysregulated system it causes a downward spiral of brake down of systems and processes. Production of substances becomes inhibited or fails, receptors become desensitised or sensitised and feedback loops of homeostasis become broken and stuck in wrong action.
PLA2R1 phospholipase A2 receptor 1 [Homo sapiens (human)] - Gene - NCBI (nih.gov)
This gene represents a phospholipase A2 receptor. The encoded protein likely exists as both a transmembrane form and a soluble form.
The transmembrane receptor may play a role in clearance of phospholipase A2, thereby inhibiting its action.
Polymorphisms at this locus have been associated with susceptibility to idiopathic membranous nephropathy. Alternatively spliced transcript variants encoding different isoforms have been identified.
Phospholipase A2 - Wikipedia
The
extracellular forms of phospholipases A2 have been isolated from different
venoms (
snake,
bee, and
wasp), from virtually every studied
mammalian tissue (including
pancreas and
kidney) as well as from
bacteria.
They require Ca2+ for activity.
Ca2+ Chemistry, Storage and Transport in Biologic Systems: An Overview - Madame Curie Bioscience Database - NCBI Bookshelf (nih.gov)
Calcium ions play a critical role in most if not all cellular processes. It has even been demonstrated that Ca2+ currents in root tips, in combination with gravity, are responsible for their downward growth.
1 Most of these effects are mediated by both temporally and spatially tightly controlled changes in cytosolic free Ca2+
brought about by activation of Ca2+ influx pathways in the cell membrane or by activation of intracellular Ca2+ release channels, and countered by transporters acting as Ca2+ pumps.
Cannabinoid receptors contribute to astroglial Ca2+-signalling and control of synaptic plasticity in the neocortex - PMC (nih.gov)
ABSTRACT
Communication between neuronal and glial cells is thought to be very important for many brain functions. Acting via release of gliotransmitters, astrocytes can modulate synaptic strength. The mechanisms underlying ATP release from astrocytes remain uncertain with exocytosis being the most intriguing and debated pathway. We have demonstrated that ATP and d-serine can be released from cortical astrocytes
in situ by a SNARE-complex-dependent mechanism. Exocytosis of ATP from astrocytes can activate post-synaptic P2X receptors in the adjacent neurons, causing a downregulation of synaptic and extrasynaptic GABA receptors in cortical pyramidal neurons. We showed that release of gliotransmitters is important for the NMDA receptor-dependent synaptic plasticity in the neocortex. Firstly, induction of
long-term potentiation (LTP) by five episodes of theta-burst stimulation (TBS) was impaired in the neocortex of dominant-negative (dn)-SNARE mice. The
LTP was rescued in the dn-SNARE mice by application of exogenous non-hydrolysable ATP analogues.
Secondly, we observed that weak sub-threshold stimulation (two TBS episodes) became able to induce LTP when astrocytes were additionally activated via CB-1 receptors. This facilitation was dependent on activity of ATP receptors and was abolished in the dn-SNARE mice.
Our results strongly support the physiological relevance of glial exocytosis for glia–neuron communications and brain function.
Control of Ca2+ influx by cannabinoid and metabotropic glutamate receptors in rat cerebellar cortex requires K+ channels - PMC (nih.gov)
Abstract
- In the rodent cerebellum, both presynaptic CB1 cannabinoid receptors and presynaptic mGluR4 metabotropic glutamate receptors acutely depress excitatory synaptic transmission at parallel fibre-Purkinje cell synapses. Using rat cerebellar slices, we have analysed the effects of selective CB1 and mGluR4 agonists on the presynaptic Ca2+ influx which controls glutamate release at this synapse.
- Changes in presynaptic Ca2+ influx were determined with the Ca2+-sensitive dyes fluo-4FF AM or fluo-3 AM. Five stimulations delivered at 100 Hz or single stimulations of parallel fibres evoked rapid and reproducible transient increases in presynaptic fluo-4FF or fluo-3 fluorescence, respectively, which decayed to prestimulus levels within a few hundred milliseconds. Bath application of the selective CB1 agonist WIN55,212-2 (1 μm) markedly reduced the peak amplitude of these fluorescence transients. This effect was fully reversed by the selective CB1 antagonist SR141716-A (1 μm).
- Bath application of the selective mGluR4 agonist l-AP4 (100 μm) also caused a transient decrease in the peak amplitude of the fluorescence transients evoked by parallel fibre stimulation.
- Bath application of the potassium channel blocker 4-AP (1 mm) totally prevented both the WIN55,212-2- and the l-AP4-induced inhibition of peak fluorescence transients evoked by parallel fibre stimulation.
- The present study demonstrates that activation of CB1 and mGluR4 receptors inhibits presynaptic Ca2+ influx evoked by parallel fibre stimulation via the activation of presynaptic K+ channels, suggesting that the molecular mechanisms underlying this inhibition involve an indirect inhibition of presynaptic voltage-gated Ca2+ channels rather than their direct inhibition.
Hypokalemia (low potassium) would also cause issues in this system of processes. Considering it is difficult to raise Potassium with low Magnesium it makes sense that we all should keep our Magnesium and potassium at good levels to avoid this.
