Pressure regulation of L-type Ca 2+ channels and its role in myogenic response

• Published in: Physiology (Bethesda, Md.) Md.), 2024-05, Vol.39 (S1)
• Main Authors: Mironova, Galina Yu, Baudel, Miguel Martín-Aragón, Flores-Tamez, Victor A., Brett, Suzanne E., Navedo, Manuel F., Welsh, Donald G.
• Format: Article
• Language: English
• ISSN: 1548-9213; 1548-9221
• DOI: 10.1152/physiol.2024.39.S1.1635

Abstract only L-type calcium (Ca 2+ ) channels hold a pivotal position in governing intracellular Ca 2+ concentration within smooth muscle and the establishment of myogenic tone. Their primary regulatory mechanism has historically been linked to voltage. Nevertheless, it remains a subject of inquiry whether voltage represents the exclusive modulator or whether these channels also exhibit mechanosensitivity. This study seeks to elucidate the influence of pressure stimuli on L-type Ca 2+ channels in the resistance arteries of rodents (rats and mice). The investigative approach spans from the scrutiny of individual smooth muscle cells employing methodologies such as whole-cell and cell-attached patch-clamp electrophysiology, immunohistochemistry, proximity ligation assay, and super-resolution microscopy to the evaluation of intact arteries utilizing pressure myography. The findings obtained through whole-cell patch-clamp electrophysiology unveil a notable augmentation in L-type Ca 2+ current in response to pressure stimuli. Subsequent scrutiny at the level of single-channel activity discloses that this augmentation is ascribed to an enhancement in functional coupling. Further inquiry reveals that the intensified functional coupling in response to pressure is contingent upon two principal factors: 1) the facilitation of cooperative gating mediated by protein kinase C (PKC), and 2) the traffcking of subunits to caveolae. Notably, functional experiments, involving depolarization elicited through the application of 30 mM KCl, underscore that arterial tone and cytosolic Ca 2+ concentration responses are markedly more pronounced when the arteries are subjected to a pressure of 80 mmHg, as opposed to 20 mmHg. The culmination of these observations from both patch-clamp experiments and functional investigations supports the assertion that L-type Ca 2+ channels are indeed amenable to mechanosensory influences, in addition to their well-documented voltage-dependent behavior. In summation, this investigation underscores that the regulatory landscape of L-type Ca 2+ channels transcends the confines of voltage control, emphasizing the significance of considering pressure sensitivity in both physiological and pathological contexts. Ongoing research endeavors aim to delineate with precision the signaling complexes within vascular smooth muscle that respond to mechanical forces. Supported by the Canadian Institute for Health Research, National Institute of Health and the Rora