Nonapeptide Hormones Oxytocin and Vasopressin Distinctly Regulate CaV1.2 L-type Calcium Channel Expression in Cardiomyocytes

Abstract

Background: The neurohypophyseal hormones oxytocin (OT) and [Arg 8 ]-vasopressin (AVP) have recently been implicated in cardiac function. This study was designed to investigate actions of OT and AVP on regulation of the voltage-gated Ca 2þ channel in cardiomyocytes.Methods and Results: Cultured neonatal rat cardiomyocytes were stimulated with OT or AVP (10 À8 M to 10 À6 M) for 24-72 h, followed by real-time PCR and patch clamp studies. Although OT did not exert any modulatory effect on L-type Ca 2þ channel current, as a shortterm effect, stimulation of cardiomyocytes with OT but not AVP decreased the expression of Ca V 1.2 mRNA with a reduced L-type Ca 2þ channel current. A transcription factor CREB mRNA expression was down-regulated by OT treatment, although T-type Ca 2þ channels (Ca V 3.1, Ca V 3.2) were unaffected by OT or AVP.Conclusion: OT but not AVP down-regulates L-type Ca 2þ channel expression through the inhibition of CREB transcriptional, suggesting a novel mechanism of OT action in the cardiac electrophysiology. (J Arrhythmia 2010; 26: 111-118)

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

“…The maximum inward I Ca.L was decreased by 20.8% ( Figure 2 B), and the maximum chord conductance (G Ca.L ) was reduced by 18.9% by long-term treatment with OT ( Figure 2 C). These electrophysiological results verified the reduction of Cav1.2 by OT ( Figure 2 A) and our previous observations [ 11 ].…”

“…The present study explored the actions of OT beyond its traditionally recognize central (e.g., social behaviors) and peripheral (e.g., uterine contraction) actions. We have previously reported that OT is a cardiovascular modulator that acts primarily to downregulate Cav1.2-L-type Ca 2+ channel, but not Cav1.3, Cav3.1, or Cav3.2 channels in cardiomyocytes [ 11 ]. In addition, OT decreased I Ca.L by the long-term effect (24–72 h), but not by the short-term effect (5 min) [ 11 ] Although these long-term effects of OT on the Cav1.2 channel was obvious, the underlying mechanism was not fully understood.…”

“…We have previously reported that OT is a cardiovascular modulator that acts primarily to downregulate Cav1.2-L-type Ca 2+ channel, but not Cav1.3, Cav3.1, or Cav3.2 channels in cardiomyocytes [ 11 ]. In addition, OT decreased I Ca.L by the long-term effect (24–72 h), but not by the short-term effect (5 min) [ 11 ] Although these long-term effects of OT on the Cav1.2 channel was obvious, the underlying mechanism was not fully understood. Here we extend our previous observations and show that OT/OTR signals stimulate the Gi protein to interfere with PKA activity to reduce CERB phosphorylation, causing a disruption of its transcription activity for Cav1.2 expression.…”

“…Real-time PCR was performed on Light Cycler (Roche) using the FastStart DNA Master SYBR Green I (Roche) as a detection reagent. The oligonucleotide primers used for real-time quantitative PCR are described in our previous reports [ 11 ]. Rat glyceraldehydes-3-phosphate dehydrogenase (GAPDH; GeneBank accession no.…”

“…Although it is well known that cardiac L-type Ca 2+ channels function is modulated by a cAMP-dependent protein kinase, little is known about the molecular mechanisms regulating L-type Ca 2+ channel gene expression in cardiomyocytes. Although we have previously demonstrated that OT downregulated the Cav1.2-L-type Ca 2+ channel expression accompanied by a reduction of I Ca.L in cardiomyocytes [ 11 ], the signal pathways underlying cardiac OT actions are poorly understood.…”