A 型腺苷受体的蛋白激酶 C 激活与调节

A adenosine receptor activation and modulation by protein kinase C.

作者信息

Gao Zhan-Guo, Levitan Ian M, Inoue Asuka, Wei Qiang, Jacobson Kenneth A

机构信息

Molecular Recognition Section, Laboratory of Bioorganic Chemistry, NIDDK, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.

Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan.

出版信息

iScience. 2023 Jun 19;26(7):107178. doi: 10.1016/j.isci.2023.107178. eCollection 2023 Jul 21.

DOI:10.1016/j.isci.2023.107178

PMID:37404375

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10316653/

Abstract

Protein kinase C (PKC) isoforms regulate many important signaling pathways. Here, we report that PKC activation by phorbol 12-myristate 13-acetate (PMA) enhanced A adenosine receptor (AR)-mediated, but not β-adrenergic receptor-mediated, cAMP accumulation, in H9C2 cardiomyocyte-like and HEK293 cells. In addition to enhancement, PKC (PMA-treatment) also activated AAR with low E (H9C2 and NIH3T3 cells endogenously expressing AAR), or with high E (AAR-overexpressing HEK293 cells) to induce cAMP accumulation. AAR activation induced by PKC was inhibited by AAR and PKC inhibitors but enhanced by AAR overexpression. Gαi isoforms and PKCγ isoform were found to be involved in both enhancement of AAR function and AAR activation. Thus, we establish PKC as an endogenous modulator and activator of AAR, involving G and PKCγ. Depending on signaling pathway, PKC could activate and enhance, or alternatively inhibit AAR activity. These findings are relevant to common functions of AAR and PKC, e.g. cardioprotection and cancer progression/treatment.

摘要

蛋白激酶C（PKC）亚型调节许多重要的信号通路。在此，我们报告，在H9C2心肌样细胞和HEK293细胞中，佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）激活PKC可增强A1腺苷受体（AR）介导的cAMP积累，但不增强β-肾上腺素能受体介导的cAMP积累。除增强作用外，PKC（经PMA处理）还可激活低亲和力的A1AR（内源性表达A1AR的H9C2和NIH3T3细胞）或高亲和力的A1AR（过表达A1AR的HEK293细胞）以诱导cAMP积累。PKC诱导的A1AR激活受到A1AR和PKC抑制剂的抑制，但A1AR过表达可增强其激活。发现Gαi亚型和PKCγ亚型参与A1AR功能的增强和A1AR的激活。因此，我们确立PKC为A1AR的内源性调节剂和激活剂，涉及Gαi和PKCγ。根据信号通路的不同，PKC可以激活和增强，或者抑制A1AR的活性。这些发现与A1AR和PKC的共同功能相关，例如心脏保护和癌症进展/治疗。