2. Academic Validation
  3. Receptor-specific contributions of caveolae, PKC, and Src tyrosine kinase to serotonergic and adrenergic regulation of Kv channels and vasoconstriction

Receptor-specific contributions of caveolae, PKC, and Src tyrosine kinase to serotonergic and adrenergic regulation of Kv channels and vasoconstriction

  • Life Sci. 2023 Jun 30;121903. doi: 10.1016/j.lfs.2023.121903.
Dong Jun Sung 1,  Solah Park 2,  Hyun Ju Noh 2,  Shadi Golpasandi 2,  Seo Hyeon Eun 2,  Hyeryeong Lee 2,  Bokyung Kim 2,  Jinhong Wie 2,  Mi Seon Seo 2,  Sang Woong Park 3,  Young Min Bae 4
Affiliations

Affiliations

  • 1 Department of Sport and Health Studies, College of Biomedical and Health Science, Konkuk University, Chungju 27478, Republic of Korea; Sports Convergence Institute, Konkuk University, Chungju 27478, Republic of Korea; Center for Metabolic Diseases, Konkuk University, Chungju 27478, Republic of Korea; Research Institute for Biomedical & Health Science, Chungju 27478, Republic of Korea.
  • 2 Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju 27478, Republic of Korea.
  • 3 Department of Emergency Medical Services, Eulji University, Seongnam 13135, Republic of Korea. Electronic address: swpark@eulji.ac.kr.
  • 4 Department of Physiology, KU Open Innovation Center, Research Institute of Medical Science, Konkuk University School of Medicine, Chungju 27478, Republic of Korea. Electronic address: ymbae30@kku.ac.kr.
PMID: 37394095 DOI: 10.1016/j.lfs.2023.121903
Abstract

Aims: Caveolae are invaginated, Ω-shaped membrane structures. They are now recognized as portals for signal transduction of multiple chemical and mechanical stimuli. Notably, the contribution of caveolae has been reported to be receptor-specific. However, details of how they differentially contribute to receptor signaling remain unclear.

Main methods: Using isometric tension measurements, patch-clamping, and western blotting, we examined the contribution of caveolae and their related signaling pathways to serotonergic (5-HT2A receptor-mediated) and adrenergic (α1-adrenoceptor-mediated) signaling in rat mesenteric arteries.

Key findings: Disruption of caveolae by methyl-β-cyclodextrin effectively blocked vasoconstriction mediated by the 5-HT2A receptor (5-HT2AR), but not by the α1-adrenoceptor. Caveolar disruption selectively impaired 5-HT2AR-mediated voltage-dependent K+ channel (Kv) inhibition, but not α1-adrenoceptor-mediated Kv inhibition. In contrast, both serotonergic and α1-adrenergic effects on vasoconstriction, as well as Kv currents, were similarly blocked by the Src tyrosine kinase inhibitor PP2. However, inhibition of protein kinase C (PKC) by either GO6976 or chelerythrine selectively attenuated the effects mediated by the α1-adrenoceptor, but not by 5-HT2AR. Disruption of caveolae decreased 5-HT2AR-mediated Src phosphorylation, but not α1-adrenoceptor-mediated Src phosphorylation. Finally, the PKC Inhibitor GO6976 blocked Src phosphorylation by the α1-adrenoceptor, but not by 5-HT2AR.

Significance: 5-HT2AR-mediated Kv inhibition and vasoconstriction are dependent on caveolar integrity and Src tyrosine kinase, but not on PKC. In contrast, α1-adrenoceptor-mediated Kv inhibition and vasoconstriction are not dependent on caveolar integrity, but rather on PKC and Src tyrosine kinase. Caveolae-independent PKC is upstream of Src activation for α1-adrenoceptor-mediated Kv inhibition and vasoconstriction.

Keywords

5-HT(2A) receptor; Caveolae; Protein kinase-C; Src tyrosine kinase; Vasoconstriction; Voltage-dependent K(+) channels (Kv); α1-adrenoceptor.

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