Hypoxic regulation of cardiac Ca2+ channel: possible role of haem oxygenase.

Abstract

Acute and chronic hypoxias are common cardiac diseases that lead often to arrhythmia and impaired contractility. At the cellular level it is unclear whether the suppression of cardiac Ca(2+) channels (Ca(V)1.2) results directly from oxygen deprivation on the channel protein or is mediated by intermediary proteins affecting the channel. To address this question we measured the early effects of hypoxia (5-60 s, P(O(2)) < 5 mmHg) on Ca(2+) current (I(Ca)) and tested the involvement of protein kinase A (PKA) phosphorylation, Ca(2+)/calmodulin-mediated signalling and the haem oxygenase (HO) pathway in the hypoxic regulation of Ca(V)1.2 in rat and cat ventricular myocytes and HEK-293 cells. Hypoxic suppression of ICa) and Ca(2+) transients was significant within 5 s and intensified in the following 50 s, and was reversible. Phosphorylation by cAMP or the phosphatase inhibitor okadaic acid desensitized I(Ca) to hypoxia, while PKA inhibition by H-89 restored the sensitivity of I(Ca) to hypoxia. This phosphorylation effect was specific to Ca(2+), but not Ba(2+) or Na(+), permeating through the channel. CaMKII inhibitory peptide and Bay K8644 reversed the phosphorylation-induced desensitization to hypoxia. Mutation of CAM/CaMKII-binding motifs of the α(1c) subunit of Ca(V)1.2 fully desensitized the Ca(2+) channel to hypoxia. Rapid application of HO inhibitors (zinc protoporphyrin (ZnPP) and tin protoporphyrin (SnPP)) suppressed the channel in a manner similar to acute hypoxia such that: (1) I(Ca) and I(Ba) were suppressed within 5 s of ZnPP application; (2) PKA activation and CaMKII inhibitors desensitized I(Ca), but not I(Ba), to ZnPP; and (3) hypoxia failed to further suppress I(Ca) and I(Ba) in ZnPP-treated myocytes. We propose that the binding of HO to the CaM/CaMKII-specific motifs on Ca(2+) channel may mediate the rapid response of the channel to hypoxia.

• Authors: Angelo O Rosa, Shahrzad Movafagh, Lars Cleemann, Martin Morad
• Journal: The Journal of physiology (J Physiol) Vol. 590 Issue 17 Pg. 4223-37 (Sep 01 2012) ISSN: 1469-7793 [Electronic] England
• PMID: 22753548 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Calcium Channels, L-Type
• Calmodulin
• Heme Oxygenase (Decyclizing)
• Cyclic AMP-Dependent Protein Kinases
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Amino Acid Sequence
• Animals
• Binding Sites
• Calcium Channels, L-Type (chemistry, genetics, metabolism)
• Calcium Signaling
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (chemistry, genetics, metabolism)
• Calmodulin (metabolism)
• Cats
• Cell Hypoxia
• Cyclic AMP-Dependent Protein Kinases (metabolism)
• HEK293 Cells
• Heme Oxygenase (Decyclizing) (antagonists & inhibitors, metabolism)
• Humans
• Hypoxia (metabolism)
• Molecular Sequence Data
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism)
• Phosphorylation
• Rats