Oxytocin Downregulates the CaV1.2 L-Type Ca2+ Channel via Gi/cAMP/PKA/CREB Signaling Pathway in Cardiomyocytes.

Masaki Morishima,Katsushige Ono,Shintaro Tahara,Yan Wang

doi:10.3390/membranes11040234

Abstract

Oxytocin (OT) and its receptor (OTR) are expressed in the heart and are involved in the physiological cardiovascular functional system. Although it is known that OT/OTR signaling is cardioprotective by reducing the inflammatory response and improving cardiovascular function, the role of OT in the cardiac electrical excitation modulation has not been clarified. This study investigates the molecular mechanism of the action of OT on cardiomyocyte membrane excitation focusing on the L-type Ca2+ channel. Our methodology uses molecular biological methods and a patch-clamp technique on rat cardiomyocytes with OT, combined with several signal inhibitors and/or activators. Our results show that long-term treatment of OT significantly decreases the expression of Cav1.2 mRNA, and reduces the L-type Ca2+ channel current (ICa.L) in cardiomyocytes. OT downregulates the phosphorylated component of a transcription factor adenosine-3′,5′-cyclic monophosphate (cAMP) response element binding protein (CREB), whose action is blocked by OTR antagonist and pertussis toxin, a specific inhibitor of the inhibitory GTP-binding regulators of adenylate cyclase, Gi. On the other hand, the upregulation of Cav1.2 mRNA expression by isoproterenol is halted by OT. Furthermore, inhibition of phospholipase C (PLC) was without effect on the OT action to downregulate Cav1.2 mRNA—which suggests a signal pathway of Gi/protein kinase A (PKA)/CREB mediated by OT/OTR. These findings indicate novel signaling pathways of OT contributing to a downregulation of the Cav1.2-L-type Ca2+ channel in cardiomyocytes.

Highlights

Oxytocin (OT) is a neurohypophyseal hormone secreted from both central and peripheral tissues, resulting in reproduction, brain neuromodulation, and central regulation of blood pressure [1]
These receptors are abundantly expressed in the heart, and local OT action in the heart is important for blood pressure regulation [2], as well as cardioprotection associated with secretion of atrial natriuretic peptide (ANP) and production of nitric oxide (NO) [3,4]
We first examined whether OT and OT receptor (OTR) could be detected in the adult rat heart and neonatal rat ventricular cardiomyocytes by using quantitative real-time PCR

Summary

Introduction

Oxytocin (OT) is a neurohypophyseal hormone secreted from both central and peripheral tissues, resulting in reproduction, brain neuromodulation, and central regulation of blood pressure [1]. OT acts upon the OT receptor (OTR), which belongs to the family of G-protein-coupled receptor (GPCRs) These receptors are abundantly expressed in the heart, and local OT action in the heart is important for blood pressure regulation [2], as well as cardioprotection associated with secretion of atrial natriuretic peptide (ANP) and production of nitric oxide (NO) [3,4]. Recent evidence indicates that OT stimulates the proliferation and differentiation of embryonic stem cells to cardiomyocytes [7] Many of these studies demonstrated that OT reduced the heart rate and the force of atrial contractions [1], the potential role of oxytocin in cardiac electrical excitation has not been intensively investigated

Methods

Results

Conclusion