Distance constraints on activation of TRPV4 channels by AKAP150-bound PKCα in arterial myocytes

The Journal of General Physiology
Sendoa TajadaLuis F Santana

Abstract

TRPV4 (transient receptor potential vanilloid 4) channels are Ca2+-permeable channels that play a key role in regulating vascular tone. In arterial myocytes, opening of TRPV4 channels creates local increases in Ca2+ influx, detectable optically as "TRPV4 sparklets." TRPV4 sparklet activity can be enhanced by the action of the vasoconstrictor angiotensin II (AngII). This modulation depends on the activation of subcellular signaling domains that comprise protein kinase C α (PKCα) bound to the anchoring protein AKAP150. Here, we used super-resolution nanoscopy, patch-clamp electrophysiology, Ca2+ imaging, and mathematical modeling approaches to test the hypothesis that AKAP150-dependent modulation of TRPV4 channels is critically dependent on the distance between these two proteins in the sarcolemma of arterial myocytes. Our data show that the distance between AKAP150 and TRPV4 channel clusters varies with sex and arterial bed. Consistent with our hypothesis, we further find that basal and AngII-induced TRPV4 channel activity decays exponentially as the distance between TRPV4 and AKAP150 increases. Our data suggest a maximum radius of action of ∼200 nm for local modulation of TRPV4 channels by AKAP150-associated PKCα.

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Citations

Jan 26, 2018·Journal of Cardiovascular Development and Disease·Tanya A Baldwin, Carmen W Dessauer
Sep 26, 2017·British Journal of Pharmacology·Lídia AmbrusBalázs István Tóth
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Oct 22, 2020·Nature Communications·Maria Paz PradaMadeline Nieves-Cintrón
Mar 19, 2021·European Journal of Obstetrics & Gynecology and Reproductive Biology: X·Daniela VillegasÉric Rousseau

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Methods Mentioned

BETA
super-resolution microscopy
electrophoresis
transfection
PCR
super-resolution nanoscopy

Software Mentioned

GATTAnalysis
MATLAB
GSD
ImageJ
TILL Image
CLAMPEX
LASAF
CellProfiler

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