ANO1, CaV1.2, and IP3R form a localized unit of EC-coupling in mouse pulmonary arterial smooth muscle.

Autor:	Akin EJ; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Aoun J; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Jimenez C; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Mayne K; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Baeck J; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Young MD; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Sullivan B; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Sanders KM; Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA., Ward SM; Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA., Bulley S; Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA., Jaggar JH; Department of Physiology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA., Earley S; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA., Greenwood IA; Department of Vascular Pharmacology, Molecular and Clinical Science Research Institute, St. George's University of London, London, UK., Leblanc N; Department of Pharmacology and Center of Biomedical Research Excellence (COBRE) for Molecular and Cellular Signal Transduction in the Cardiovascular System , Reno, NV, USA.
Jazyk:	angličtina
Zdroj:	The Journal of general physiology [J Gen Physiol] 2023 Nov 06; Vol. 155 (11). Date of Electronic Publication: 2023 Sep 13.
DOI:	10.1085/jgp.202213217
Abstrakt:	Pulmonary arterial (PA) smooth muscle cells (PASMC) generate vascular tone in response to agonists coupled to Gq-protein receptor signaling. Such agonists stimulate oscillating calcium waves, the frequency of which drives the strength of contraction. These Ca2+ events are modulated by a variety of ion channels including voltage-gated calcium channels (CaV1.2), the Tmem16a or Anoctamin-1 (ANO1)-encoded calcium-activated chloride (CaCC) channel, and Ca2+ release from the sarcoplasmic reticulum through inositol-trisphosphate receptors (IP3R). Although these calcium events have been characterized, it is unclear how these calcium oscillations underly a sustained contraction in these muscle cells. We used smooth muscle-specific ablation of ANO1 and pharmacological tools to establish the role of ANO1, CaV1.2, and IP3R in the contractile and intracellular Ca2+ signaling properties of mouse PA smooth muscle expressing the Ca2+ biosensor GCaMP3 or GCaMP6. Pharmacological block or genetic ablation of ANO1 or inhibition of CaV1.2 or IP3R, or Ca2+ store depletion equally inhibited 5-HT-induced tone and intracellular Ca2+ waves. Coimmunoprecipitation experiments showed that an anti-ANO1 antibody was able to pull down both CaV1.2 and IP3R. Confocal and superresolution nanomicroscopy showed that ANO1 coassembles with both CaV1.2 and IP3R at or near the plasma membrane of PASMC from wild-type mice. We conclude that the stable 5-HT-induced PA contraction results from the integration of stochastic and localized Ca2+ events supported by a microenvironment comprising ANO1, CaV1.2, and IP3R. In this model, ANO1 and CaV1.2 would indirectly support cyclical Ca2+ release events from IP3R and propagation of intracellular Ca2+ waves. (© 2023 Akin et al.)
Databáze:	MEDLINE
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