title: Flow-induced activation of TRPV5 and TRPV6 channels stimulates Ca(2+)-activated K(+) channel causing membrane hyperpolarization.
abstract: TRPV5 and TRPV6 channels are expressed in distal renal tubules and play important roles in the transcellular Ca(2+) reabsorption in kidney. They are regulated by multiple intracellular factors including protein kinases A and C, membrane phospholipid PIP2, protons, and divalent ions Ca(2+) and Mg(2+). Here, we report that fluid flow that generates shear force within the physiological range of distal tubular fluid flow activated TRPV5 and TRPV6 channels expressed in HEK cells. Flow-induced activation of channel activity was reversible and did not desensitize over 2min. Fluid flow stimulated TRPV5 and 6-mediated Ca(2+) entry and increased intracellular Ca(2+) concentration. N-glycosylation-deficient TRPV5 channel was relatively insensitive to fluid flow. In cells coexpressing TRPV5 (or TRPV6) and Slo1-encoded maxi-K channels, fluid flow induced membrane hyperpolarization, which could be prevented by the maxi-K blocker iberiotoxin or TRPV5 and 6 blocker La(3+). In contrast, fluid flow did not cause membrane hyperpolarization in cells coexpressing ROMK1 and TRPV5 or 6 channel. These results reveal a new mechanism for the regulation of TRPV5 and TRPV6 channels. Activation of TRPV5 and TRPV6 by fluid flow may play a role in the regulation of flow-stimulated K(+) secretion via maxi-K channels in distal renal tubules and in the mechanism of pathogenesis of thiazide-induced hypocalciuria.
authors.affiliation: Department of Physiology, Institute of Lifestyle Medicine and Nuclear Receptor Research Consortium, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: skcha@yonsei.ac.kr.
authors.forename: Seung-Kuy
authors.initials: SK
authors.lastname: Cha
authors.affiliation: Department of Physiology, Institute of Lifestyle Medicine and Nuclear Receptor Research Consortium, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
authors.forename: Ji-Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: Chou-Long.Huang@UTSouthwestern.edu.
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
mesh_terms: D002118:Calcium / Q000378:metabolism; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008564:Membrane Potentials; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D012212:Rheology; D013314:Stress, Mechanical; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D024661:Potassium Channels, Inwardly Rectifying; D050916:TRPV Cation Channels; C120776:TRPV6 channel; D002118:Calcium
keywords: Ca(2+)-activated K(+) channel; Flow-mediated Ca(2+) entry; Flow-mediated K(+) secretion; ROMK; TRPV5; TRPV6