Capsaicin modulates acetylcholine release at the myoneural junction

Abstract

Transient receptor potential (TRP) proteins are non-selective cation channel proteins that are expressed throughout the body. Previous studies demonstrated the expression of TRP Vanilloid 1 (TRPV1), capsaicin (CAP) receptor, in sensory neurons. Recently, we reported TRPV1 expression in mouse motor nerve terminals [MNTs; (Thyagarajan et al., 2009)], where we observed that CAP protected MNTs from botulinum neurotoxin A (BoNT/A). Phrenic nerve diaphragm nerve muscle preparations (NMP) isolated from isoflurane anesthetized adult mice were analyzed for twitch tension, spontaneous (mEPCs) and nerve stimulus evoked (EPCs) acetylcholine release. When acutely applied to isolated NMP, CAP produced a concentration-dependent decline of twitch tension and produced a significant decline in the amplitude of EPCs and quantal content without any effect on the mEPCs. The suppression of nerve stimulus evoked acetylcholine release by CAP was antagonized by capsazepine (CPZ), a TRPV1 antagonist. CAP did not suppress phrenic nerve stimulus evoked acetylcholine release in TRPV1 knockout mice. Also, CAP treatment, in vitro, interfered with the localization of adapter protein 2 in cholinergic Neuro 2a cells. Wortmannin, (WMN; non-selective phosphoinositol kinase inhibitor), mimicked the effects of CAP by inhibiting the acetylcholine exocytosis. Our data suggest that TRPV1 proteins expressed at the MNT are coupled to the exo-endocytic mechanisms to regulate neuromuscular functions.

Metabotropic GABAB receptors mediate GABA inhibition of acetylcholine release in the rat neuromuscular junction

“…This mechanism probably involves hydrolysis of phosphatidyl inositol (4,5) bisphosphate (PIP2) to form inositol trisphosphate and diacylglycerol via the GABA B receptor-mediated activation of PLC. There are some studies supporting this hypothesis: (i) activation of the transient receptor potential vanilloid 1 (TRPV1) channels is capable of causing a PLC-dependent PIP2 hydrolysis (Lukacs et al 2007); (ii) TRPV1 channels have been revealed in rat neuromuscular junction and their activation by capsaicin results in a selective decrease in the quantal content of stimulus evoked neurotransmitter release (as in our case) and does not influence the processes of spontaneous quantal release of ACh (Thyagarajan et al 2014). Authors of the latter paper concluded that the decrease in the membrane PIP2 level, as a function of TRPV1-PLCdependent mechanisms, is the major reason for selective depression of evoked exocytosis of ACh.…”

“…); (ii) TRPV1 channels have been revealed in rat neuromuscular junction and their activation by capsaicin results in a selective decrease in the quantal content of stimulus evoked neurotransmitter release (as in our case) and does not influence the processes of spontaneous quantal release of ACh (Thyagarajan et al . ). Authors of the latter paper concluded that the decrease in the membrane PIP2 level, as a function of TRPV1‐PLC‐dependent mechanisms, is the major reason for selective depression of evoked exocytosis of ACh.…”

“…; Thyagarajan et al . ) were revealed, as well as the mechanisms of the opposite regulation of these forms of quantal neurotransmitter release (Pan et al . ; Wasser et al .…”

“…However, to date a number of experimental facts have accumulated indicating the possibility that spontaneous and evoked forms of neurotransmission are independent neuronal signal transduction pathways (Ramirez and Kavalali 2011;Walter et al 2014). Therefore, specific mechanisms of selective regulation of solely spontaneous (Taniguchi et al 2000;Glitsch 2006;Pratt et al 2011) or evoked release (Gaydukov et al 2014;Thyagarajan et al 2014) were revealed, as well as the mechanisms of the opposite regulation of these forms of quantal neurotransmitter release (Pan et al 1996;Wasser et al 2007). Furthermore, data were obtained suggesting that the processes of spontaneous and evoked quantal release of the neurotransmitter may differ by molecular fusion mechanisms (De ak et al 2006;Maximov et al 2007;Zhou et al 2013) or by spots of quanta released within the boundaries of the same synapse (Ramirez and Kavalali 2011;Melom et al 2013).…”

CAP and Metabolic Diseases: A Mini Review on Preclinical Mechanisms and Clinical Efficacy

“…Primarily, the expression of TRPV1 is recognized in sensory neurons. Published literature suggests that TRPV1 is also expressed in various other tissues such as the neuromuscular junction [2][3][4], adipose tissue [5][6][7], liver [8,9], skeletal muscle [10,11], vascular smooth muscle [12], etc. Also, published work suggests that TRPV1 in the brain.…”