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Published on: July 20, 2012
Hypoxic regulation of cardiac Ca2+ channel: possible role of haem oxygenase
Angelo O Rosa1, Shahrzad Movafagh, Lars Cleemann
1Cardiac Signaling Center of University of South Carolina, Medical University of South Carolina and Clemson University, Charleston, SC 29245, USA.
Insights
Hypoxia rapidly suppresses cardiac calcium channels (CaV1.2) via the heme oxygenase (HO) pathway, involving protein kinase A (PKA) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) signaling, affecting heart contractility.
Area of Science:
- Cardiology
- Cellular Physiology
- Molecular Biology
Background:
- Hypoxia is a common cardiac condition leading to arrhythmia and impaired contractility.
- The precise cellular mechanisms by which oxygen deprivation affects cardiac calcium channels (CaV1.2) remain unclear.
- Investigating the role of intermediary signaling pathways is crucial for understanding hypoxic cardiac dysfunction.
Purpose of the Study:
- To elucidate the rapid cellular mechanisms underlying hypoxia-induced suppression of cardiac CaV1.2 channels.
- To determine the involvement of protein kinase A (PKA), Ca2+/calmodulin-mediated signaling, and the heme oxygenase (HO) pathway in hypoxic CaV1.2 regulation.
- To differentiate between direct oxygen effects on the channel protein versus indirect signaling mediation.
Main Methods:
- Measurement of Ca2+ current (ICa) and Ca2+ transients in rat and cat ventricular myocytes and HEK-293 cells under acute hypoxia (5-60 seconds).
- Pharmacological manipulation of PKA, CaMKII, and HO pathways using inhibitors and activators.
- Site-directed mutagenesis of CaMKII-binding motifs on the CaV1.2 α1c subunit.
Main Results:
- Acute hypoxia rapidly suppressed ICa and Ca2+ transients within 5 seconds, with effects intensifying over 50 seconds and being reversible.
- PKA phosphorylation desensitized ICa to hypoxia, an effect reversed by PKA inhibition, indicating a role for PKA in hypoxic response modulation.
- Heme oxygenase (HO) inhibition mimicked hypoxia's rapid suppression of ICa and IBa, and hypoxia did not further suppress ICa in HO-inhibited cells, suggesting HO mediates the rapid hypoxic effect.
- Mutation of CaMKII-binding sites on CaV1.2 abolished the channel's sensitivity to hypoxia.
Conclusions:
- The heme oxygenase (HO) pathway, acting through Ca2+/calmodulin-dependent protein kinase II (CaMKII) binding sites on the CaV1.2 channel, mediates the rapid suppression of cardiac calcium channels during acute hypoxia.
- Protein kinase A (PKA) phosphorylation plays a modulatory role in the channel's response to hypoxia.
- These findings reveal a novel signaling cascade linking oxygen sensing to cardiac electrophysiology, offering potential therapeutic targets for hypoxic heart disease.
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.
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