4.7 Article

Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation

期刊

JOURNAL OF NEUROSCIENCE
卷 25, 期 49, 页码 11322-11329

出版社

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3006-05.2005

关键词

bradykinin; TRPM8; TRPV1; nociceptor; synaptic transmission; protein kinase C; channel; c-fiber

资金

  1. NIDDK NIH HHS [R56 DK065742, R01 DK065742, DK065742] Funding Source: Medline
  2. NINDS NIH HHS [NS042296] Funding Source: Medline

向作者/读者索取更多资源

Transient receptor potential melastatin 8 (TRPM8) and transient receptor potential vanilloid 1 (TRPV1) are ion channels that detect cold and hot sensations, respectively. Their activation depolarizes the peripheral nerve terminals resulting in action potentials that propagate to brain via the spinal cord. These receptors also play a significant role in synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons. Here, we show that TRPM8 is functionally downregulated by activation of protein kinase C (PKC) resulting in inhibition of membrane currents and increases in intracellular Ca2+ compared with upregulation of TRPV1 in cloned and native receptors. Bradykinin significantly downregulates TRPM8 via activation of PKC in DRG neurons. Activation of TRPM8 or TRPV1 at first sensory synapse between DRG and DH neurons leads to a robust increase in frequency of spontaneous/miniature EPSCs. PKC activation blunts TRPM8- and facilitates TRPV1-mediated synaptic transmission. Significantly, downregulation is attributable to PKC-mediated dephosphorylation of TRPM8 that could be reversed by phosphatase inhibitors. These findings suggest that inflammatory thermal hyperalgesia mediated by TRPV1 may be further aggravated by downregulation of TRPM8, because the latter could mediate the much needed cool/soothing sensation.

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