Abstract
Transient receptor potential (TRP) ion channels in peripheral sensory neurons are functionally regulated by hydrolysis of the phosphoinositide PI(4,5)P2 and changes in the level of protein kinase mediated phosphorylation following activation of various G protein coupled receptors. We now show that the activity of TRPM3 expressed in mouse dorsal root ganglion (DRG) neurons is inhibited by agonists of the Gi-coupled µ opioid, GABA-B and NPY receptors. These agonist effects are mediated by direct inhibition of TRPM3 by Gβγ subunits, rather than by a canonical cAMP mediated mechanism. The activity of TRPM3 in DRG neurons is also negatively modulated by tonic, constitutive GPCR activity as TRPM3 responses can be potentiated by GPCR inverse agonists. GPCR regulation of TRPM3 is also seen in vivo where Gi/o GPCRs agonists inhibited and inverse agonists potentiated TRPM3 mediated nociceptive behavioural responses.
Highlights
Proteins encoded by the TRPM3 gene form non-selective cation channels which are widely expressed in mammalian tissues
TRPM3 is expressed in dorsal root ganglion (DRG) neurons where it plays a role in the transduction of thermal stimuli in normal conditions and notably in the development of heat hypersensitivity in inflammatory conditions (Vriens et al, 2011)
Studies of TRPM3 have been facilitated by the discovery of pregnenolone sulphate (PS) and the synthetic compound CIM0216 as TRPM3 agonists (Wagner et al, 2008; Held et al, 2015) that can be used to probe the functions and characteristics of TRPM3, and we have utilised these compounds to investigate the regulation of TRPM3 channels by G-protein coupled receptors (GPCRs) ligands
Summary
Proteins encoded by the TRPM3 gene form non-selective cation channels which are widely expressed in mammalian tissues. Like other TRP channels, TRPM3 can be regulated by phosphoinositol 4,5bisphosphate (PI(4,5)P2) and other phosphoinositides as loss or hydrolysis of PI(4,5)P2 leads to a reduction in TRPM3 activity that can be restored by application of exogenous PI(4,5) P2 (Badheka et al, 2015; Toth et al, 2015). These findings suggest that TRPM3 activity can be regulated downstream of activation of Gq coupled GPCRs. A human TRPM3 variant with a short carboxyl terminus was found to be insensitive to stimulation of Gq-coupled muscarinic receptors or histamine H1 receptors (Grimm et al, 2003). Activation of Gaq-linked receptors inhibits TRPM8 via a direct action of the Gaq subunit with the TRPM8 channel (Zhang et al, 2012)
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