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G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons.

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 G_i-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 G_i/o GPCRs agonists inhibited and inverse agonists potentiated TRPM3 mediated nociceptive behavioural responses.

SUBMITTER: Quallo T

PROVIDER: S-EPMC5593501 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons.

Quallo Talisia T Alkhatib Omar O Gentry Clive C Andersson David A DA Bevan Stuart S

eLife 20170815

Transient receptor potential (TRP) ion channels in peripheral sensory neurons are functionally regulated by hydrolysis of the phosphoinositide PI(4,5)P<sub>2</sub> 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 G<sub>i</sub>-coupled µ opioid, GABA-B and NPY receptors. These agonist effects ar ...[more]

PMID: 28826490

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Project description:Abstract Acid-sensing ion channels (ASICs) play a critical role in nociception in human sensory neurons. Four genes (ASIC1, ASIC2, ASIC3, and ASIC4) encoding multiple subunits through alternative splicing have been identified in humans. Real time-PCR experiments showed strong expression of three subunits ASIC1, ASIC2, and ASIC3 in human dorsal root ganglia; however, their detailed expression pattern in different neuronal populations has not been investigated yet. In the current study, using an in situ hybridization approach (RNAscope), we examined the presence of ASIC1, ASIC2, and ASIC3 mRNA in three subpopulations of human dorsal root ganglia neurons. Our results revealed that ASIC1 and ASIC3 were present in the vast majority of dorsal root ganglia neurons, while ASIC2 was only expressed in less than half of dorsal root ganglia neurons. The distribution pattern of the three ASIC subunits was the same across the three populations of dorsal root ganglia neurons examined, including neurons expressing the REarranged during Transfection (RET) receptor tyrosine kinase, calcitonin gene-related peptide, and a subpopulation of nociceptors expressing Transient Receptor Potential Cation Channel Subfamily V Member 1. These results strongly contrast the expression pattern of Asics in mice since our previous study demonstrated differential distribution of Asics among the various subpopulation of dorsal root ganglia neurons. Given the distinct acid-sensitivity and activity dynamics among different ASIC channels, the expression differences between human and rodents should be taken under consideration when evaluating the translational potential and efficiency of drugs targeting ASICs in rodent studies. Papalampropoulou-Tsiridou et al. report broad expression of Acid sensing Ion Channel (ASIC) 1 and ASIC3 subunits in human primary sensory neurons. Moreover, the relative distribution of ASICs was constant across neuronal subpopulations, contrasting with expression patterns in rodents. These differences should be taken under consideration when evaluating the translational potential of ASICs studies in rodents. Graphical Abstract Graphical abstract

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G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons.

Publications

G protein βγ subunits inhibit TRPM3 ion channels in sensory neurons.

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