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Dynamic Response of Arterial Cerebral Ca V 1.2 Channels to Intravascular Pressure
Author(s) -
Mironova Galina,
Baudel Miguel,
FloresTamez Victor,
Navedo Manuel,
Welsh Donald
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02824
Subject(s) - mechanosensitive channels , caveolae , electrophysiology , gating , biophysics , vascular smooth muscle , cav1.2 , myogenic contraction , microbiology and biotechnology , bapta , depolarization , patch clamp , neuroscience , chemistry , biology , intracellular , ion channel , medicine , signal transduction , voltage dependent calcium channel , endocrinology , calcium , biochemistry , smooth muscle , receptor
Intravascular pressure elicits arterial constriction by elevating intracellular [Ca 2+ ] in vascular smooth muscle cells (SMCs). Past studies have argued that this rise is singularly linked to depolarization and the voltage‐dependent gating of L‐type (Ca V 1.2) Ca 2+ channels. While important, pressure might also directly modulate Ca V 1.2 activity by promoting functional coupling among subunits, a response that enhances Ca 2+ sparklets generation. In this regard, the study goal was to define the mechanosensitivity of Ca V 1.2 channels using a range of electrophysiological approaches. Beginning with whole‐cell patch clamp electrophysiology, we show that SMCs stretching by a hypoosmotic challenge (from 300 to 200 mOsm) leads to a marked rise in total Ca 2+ current (around 40%) without changing voltage‐dependent activation/inactivation properties. This mechanosensitive response reflects augmented functional coupling, as revealed through recordings of single channel activity. Ongoing work has further revealed that the rise in functional coupling was intimately linked to caveolin‐1, caveolae forming membrane protein tied to the cytoskeleton dynamics and signal transduction. This protein‐protein relationship was also observed at the immunohistochemical level, with the proximity ligation assay showing that Ca V 1.2 colocalizes with caveolin‐1 when SMCs are stretched by the hypoosmotic challenge. In closing, the current work reveals that Ca V 1.2 channels are a dynamic target of intravascular pressure and likely integral to a robust myogenic response. Continuing work will define the composition of the pressure‐sensitive signaling complex and how it is impacted by disease.