Molecular pathways of oestrogen receptors and β-adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

Abstract

Oestrogen receptors (ERs) and β-adrenergic receptors (βARs) play important roles in the cardiovascular system. Moreover, these receptors are expressed in cardiac myocytes and vascular tissues. Numerous experimental observations support the hypothesis that similarities and interactions exist between the signalling pathways of ERs (ERα, ERβ and GPR30) and βARs (β1AR, β2AR and β3AR). The recently discovered oestrogen receptor GPR30 shares structural features with the βARs, and this forms the basis for the interactions and functional overlap. GPR30 possesses protein kinase A (PKA) phosphorylation sites and PDZ binding motifs and interacts with A-kinase anchoring protein 5 (AKAP5), all of which enable its interaction with the βAR pathways. The interactions between ERs and βARs occur downstream of the G-protein-coupled receptor, through the Gαs and Gαi proteins. This review presents an up-to-date description of ERs and βARs and demonstrates functional synergism and interactions among these receptors in cardiac cells. We explore their signalling cascades and the mechanisms that orchestrate their interactions and propose new perspectives on the signalling patterns for the GPR30 based on its structural resemblance to the βARs. In addition, we explore the relevance of these interactions to cell physiology, drugs (especially β-blockers and calcium channel blockers) and cardioprotection. Furthermore, a receptor-independent mechanism for oestrogen and its influence on the expression of βARs and calcium-handling proteins are discussed. Finally, we highlight promising therapeutic avenues that can be derived from the shared pathways, especially the phosphatidylinositol-3-OH kinase (PI3K/Akt) pathway.