 | Membrane Stretch-Induced Activation of a TRPM4-Like Nonselective Cation Channel in Cerebral Artery Myocytes
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| | Hiromitsu Morita1)2)3), Akira Honda1)4), Ryuji Inoue4), Yushi Ito2), Kihachiro Abe3), Mark T. Nelson1) and Joseph E. Brayden1) |
| 1) Department of Pharmacology, College of Medicine, University of Vermont, USA
2) Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, Japan
3) Special Patient Oral Care Unit, Kyushu University Hospital, Japan
4) Department of Physiology, School of Medicine, Fukuoka University, Japan |
| ABSTRACT: Stretch-activated cation channels (SACs) have been observed in many types of smooth muscle cells. However, the molecular identity and activation mechanisms of SACs remain poorly understood. We report that TRPM4-like cation channels are activated by membrane stretch in rat cerebral artery myocytes (CAMs). Negative pressure (≥20 mmHg, cell-attached mode) activated single channels (approximately 20 pS) in isolated CAMs. These channels were permeable to Na+ and Cs+ and inhibited by Gd3+ (30 μM) and DIDS (100 μM). The effect of negative pressure was abolished by membrane excision, but subsequent application of Ca2+ (>100 nM) to the intracellular side of the membrane restored single channel activity that was indistinguishable from SACs. Caffeine (5 mM), which depletes SR Ca2+-stores, first activated and then abolished SACs. Tetracaine (100 μM), a ryanodine receptor antagonist, inhibited SACs. Overexpression of hTRPM4B in HEK293 cells resulted in the appearance of cation channels that were activated by both negative pressure and Ca2+ and which had very similar biophysical and pharmacological properties as compared with SACs in CAMs. These studies indicate that TRPM4-like channels in CAMs can be activated by membrane stretch, possibly through ryanodine receptor activation, and this may contribute to the depolarization and concomitant vasoconstriction of intact cerebral arteries following mechanical stimulation.
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| | Keywords: | TRPM4, stretch, cation channel, cerebral artery, smooth muscle |
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