H

^aThis paper is dedicated to the memory of our friend and colleague Dr. Guy Champigny, who has contributed in a major way to our current understanding of the properties of this ion channel family.
^bCorresponding author. Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France. Phone: 33 (0)4 93 95 77 02 OR 03; fax: 33 (0)4 93 95 77 04; e-mail: ipmc{at}ipmc.cnrs.fr

H⁺-gated cation channels are members of a new family of ionicchannels, which includes the epithelial Na⁺ channel and theFMRFamide-activated Na⁺ channel. ASIC, the first member of theH⁺-gated Na⁺ channel subfamily, is expressed in brain and dorsalroot ganglion cells (DRGs). It is activated by pHe variationsbelow pH 7. The presence of this channel throughout the brainsuggests that the H⁺ might play an essential role as a neurotransmitteror neuromodulator. The ASIC channel is also present in dorsalroot ganglion cells, as is its homolog DRASIC, which is specificallypresent in DRGs and absent in the brain. Since external acidificationis a major factor in pain associated with inflammation, hematomas,cardiac or muscle ischemia, or cancer, these two channel proteinsare potentially central players in pain perception. ASIC activatesand inactivates rapidly, while DRASIC has both a fast and sustainedcomponent. Other members of this family such as MDEG1 and MDEG2are either H⁺-gated Na⁺ channels by themselves (MDEG1) or modulatorsof H⁺-gated channels formed by ASIC and DRASIC. MDEG1 is ofparticular interest because the same mutations that produceselective neurodegeneration in C. elegans mechanosensitive neurons,when introduced in MDEG1, also produce neurodegeneration. MDEG2is selectively expressed in DRGs, where it assembles with DRASICto radically change its biophysical properties, making it similarto the native H⁺-gated channel, which is presently the bestcandidate for pain perception.

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[Abstract] [Full Text]