4.7 Article

The Ca2+/CaM, Src kinase and/or PI3K-dependent EGFR transactivation via 5-HT2A and 5-HT1B receptor subtypes mediates 5-HT-induced vasoconstriction

Journal

BIOCHEMICAL PHARMACOLOGY
Volume 206, Issue -, Pages -

Publisher

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2022.115317

Keywords

5-HT receptor subtypes; EGFR; Transactivation; Vascular smooth muscle

Funding

  1. TUBITAK
  2. [111S131]

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The interaction between serotonin receptors and epidermal growth factor receptors (EGFR) was investigated in this study, with a focus on their role in vascular constriction. It was found that EGFR, Src, and PI3K play a role in serotonin-induced vasoconstriction, especially in the mesenteric artery. The upstream mediators of EGFR transactivation by serotonin were identified as Ca2+/CaM, Src, and PI3K, with Erk1/2 and Akt activation playing a partial role. Furthermore, different subtypes of serotonin receptors (5-HT2A and 5-HT1B) have varying effects on EGFR transactivation through Src and/or PI3K, with 5-HT2A having a greater impact than 5-HT1B receptors.
G protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTK) modulate vascular tone and contraction via rapid and long-term processes. Sustained activation of these receptor types can change vascular structure, and the ability of vasculature to adapt to high pressure. In this study, the interaction between serotonin (5-HT) re-ceptors and epidermal growth factor receptors (EGFR) on vasoconstriction and the mechanisms of EGFR transactivation and its downstream mediators were investigated. We measured 5-HT-induced vasoconstriction in the aorta and the mesenteric artery; and the effects of EGFR, Src and PI3K, and their downstream mediators Erk1/2 and Akt phosphorylation on 5-HT-mediated vasoconstriction in the presence or absence of pharmaco-logical inhibitors of Ca2+/CaM, EGFR, Src, and PI3K. Furthermore, we determined the contribution of 5-HT receptor subtypes to 5-HT-induced vasoconstriction and EGFR transactivation using selective 5-HT2A and 5-HT1B receptors ligands. Our results show that EGFR, Src, and PI3K are involved in 5-HT-induced vasoconstriction both in the aorta and the mesenteric artery, and that these kinases have a more prominent role in the mesenteric artery than the aorta. With regard to EGFR transactivation by 5-HT, Ca2+/CaM, Src and PI3K are upstream mediators, and transactivation is partly mediated by Erk1/2 and Akt activation. Furthermore, Ca2+/CaM, Src, and PI3K are the main regulators for Akt activation, however Src only has a prominent role for Erk1/2 activation. 5-HT2A and 5-HT1B receptors have different EGFR transactivation profiles through Src and/or PI3K, with 5-HT2A having a greater role than 5-HT1B receptors.

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