Role of Connexin 43 phosphorylation on Serine-368 by PKC in cardiac function and disease

Renju Pun; Michael H Kim; Brian J North

doi:10.3389/fcvm.2022.1080131

Role of Connexin 43 phosphorylation on Serine-368 by PKC in cardiac function and disease

Front Cardiovasc Med. 2023 Jan 12:9:1080131. doi: 10.3389/fcvm.2022.1080131. eCollection 2022.

Authors

Renju Pun¹, Michael H Kim², Brian J North¹

Affiliations

¹ Department of Biomedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States.
² CHI Health Heart Institute, School of Medicine, Creighton University, Omaha, NE, United States.

Abstract

Intercellular communication mediated by gap junction channels and hemichannels composed of Connexin 43 (Cx43) is vital for the propagation of electrical impulses through cardiomyocytes. The carboxyl terminal tail of Cx43 undergoes various post-translational modifications including phosphorylation of its Serine-368 (S368) residue. Protein Kinase C isozymes directly phosphorylate S368 to alter Cx43 function and stability through inducing conformational changes affecting channel permeability or promoting internalization and degradation to reduce intercellular communication between cardiomyocytes. Recent studies have implicated this PKC/Cx43-pS368 circuit in several cardiac-associated diseases. In this review, we describe the molecular and cellular basis of PKC-mediated Cx43 phosphorylation and discuss the implications of Cx43 S368 phosphorylation in the context of various cardiac diseases, such as cardiomyopathy, as well as the therapeutic potential of targeting this pathway.

Keywords: Connexin 43; cardiac disease; cardiology; gap junctions; phosphorylation; protein kinase C.

Publication types

Review

Grants and funding

This work was supported by the Nebraska Department of Health and Human Services (DHHS) (LB692) and Creighton University Health Science Strategic Investment Fund Faculty Development Grant to BN. Through LB692, this work was supported by revenue from Nebraska’s excise tax on cigarettes awarded to BN of Creighton University through the Nebraska Department of Health and Human Services (DHHS). Its contents represent the view(s) of the author(s) and do not necessarily represent the official views of the State of Nebraska or DHHS.