Journal club 2012-09-13

ncb2529

ncb2529-s1

Direct inhibition of the cold-activated TRPM8 ion channel by Gα(q).

Source

Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.

Abstract

Activation of the TRPM8 ion channel in sensory nerve endings produces a sensation of pleasant coolness. Here we show that inflammatory mediators such as bradykinin and histamine inhibit TRPM8 in intact sensory nerves, but do not do so through conventional signalling pathways. The G-protein subunit Gα(q) instead binds to TRPM8 and when activated by a Gq-coupled receptor directly inhibits ion channel activity. Deletion of Gα(q) largely abolished inhibition of TRPM8, and inhibition was rescued by a Gα(q) chimaera whose ability to activate downstream signalling pathways was completely ablated. Activated Gα(q) protein, but not Gβγ, potently inhibits TRPM8 in excised patches. We conclude that Gα(q) pre-forms a complex with TRPM8 and inhibits activation of TRPM8, following activation of G-protein-coupled receptors, by a direct action. This signalling mechanism may underlie the abnormal cold sensation caused by inflammation.

PMID:

 22750945

[PubMed – in process] PMCID:

PMC3428855 [Available on 2013/2/1]

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Journal club 2012-07-26

Emery.SOM
Filename : emery-som.pdf (907 KB)
Caption :
Science-2011-Emery-1462-6
Filename : science-2011-emery-1462-6.pdf (426 KB)
Caption :

Science. 2011 Sep 9;333(6048):1462-6.

HCN2 ion channels play a central role in inflammatory and neuropathic pain.

Source

Department of Pharmacology, University of Cambridge, Cambridge CB2 1PD, UK.

Abstract

The rate of action potential firing in nociceptors is a major determinant of the intensity of pain. Possible modulators of action potential firing include the HCN ion channels, which generate an inward current, I(h), after hyperpolarization of the membrane. We found that genetic deletion of HCN2removed the cyclic adenosine monophosphate (cAMP)-sensitive component of I(h) and abolished action potential firing caused by an elevation of cAMP in nociceptors. Mice in which HCN2 was specifically deleted in nociceptors expressing Na(V)1.8 had normal pain thresholds, but inflammation did not cause hyperalgesia to heat stimuli. After a nerve lesion, these mice showed no neuropathic pain in response to thermal or mechanical stimuli. Neuropathic pain is therefore initiated by HCN2-driven action potential firing in Na(V)1.8-expressing nociceptors.

PMID:

 21903816

[PubMed – indexed for MEDLINE]

 

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