Abstract
The neuronal glycine transporter GlyT2 modulates inhibitory glycinergic neurotransmission and plays a key role in regulating nociceptive signal progression. The cholinergic system acting through muscarinic acetylcholine receptors (mAChRs) also mediates important regulations of nociceptive transmission being the M2 subtype the most abundantly expressed in the spinal cord. Here we studied the effect of M2 mAChRs stimulation on GlyT2 function co-expressed in a heterologous system with negligible levels of muscarinic receptor activity. We found GlyT2 is down-regulated by carbachol in a calcium-dependent manner. Different components involved in cell calcium homeostasis were analysed to establish a role in the mechanism of GlyT2 inhibition. GlyT2 down-regulation by carbachol was increased by thapsigargin and reduced by internal store depletion, although calcium release from endoplasmic reticulum or mitochondria had a minor role on GlyT2 inhibition. Our results are consistent with a GlyT2 sensitivity to intracellular calcium mobilized by M2 mAChRs in the subcortical area of the plasma membrane. A crucial role of the plasma membrane sodium calcium exchanger NCX is proposed.
Highlights
Glycine is the main inhibitory neurotransmitter in caudal areas of the central nervous system (CNS) and controls the processing of motor, sensory and nociceptive information
In order to know if GlyT2 was sensitive to calcium released from the endoplasmic reticulum (ER) and this had a role in the inhibition by carbachol, we addressed the main ER pathways for the release of Ca2+: the inositol triphosphate (IP3) pathway, which can be activated by some G-protein-coupled receptors including M1 and M3 muscarinic acetylcholine receptors (mAChRs) subtypes, and the calcium-induced calcium release (CICR), in which ryanodine receptors (RyRs) are involved [31]
In this work we have studied the down-regulation of GlyT2 exerted by the major mAChR subtype in the spinal dorsal glycine transport
Summary
Glycine is the main inhibitory neurotransmitter in caudal areas of the central nervous system (CNS) and controls the processing of motor, sensory and nociceptive information. Glycinergic neurons present in the dorsal horn of the spinal cord diminish their activity in Esperanza Jiménez and Amparo Fornés have Contributed to the work
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