L-type calcium channel as a cardiac oxygen sensor.
Acute oxygen sensing in the heart is thought to occur through redox regulation and phosphorylation of membrane channels. Here we report a novel O2-sensing mechanism involving the C-terminus of the L-type Ca2+ channel and regulated by PKA phosphorylation. In patch-clamped myocytes, oxygen deprivation decreased ICa within 40 s. The suppressive effect of anoxia was relieved by PKA-mediated phosphorylation only when Ca2+ was the charge carrier, whereas phosphorylated IBa remained sensitive to O2 withdrawal. Suppression of Ca2+ release by thapsigargin did not alter the response of ICa to anoxia, suggesting a mandatory role for Ca2+ influx and not Ca2+-induced Ca2+ release (CICR) in O2 regulation of the channel. Consistent with this idea, mutation of 80 amino acids in the Ca2+/CaM-binding domain of the recombinant alpha1C subunit that removes Ca2+ dependent inactivation (CDI) abolished O2 sensitivity of the channel. Our findings suggest that the Ca2+/CaM binding domain of the L-type Ca2+ may represent a molecular site for O2 sensing of the heart.
Movafagh
Shahrzad
S
Cardiac Signaling Center, University of South Carolina, Charleston, South Carolina 29403, USA.
Morad
Martin
M
D000595:Amino Acid Sequence; D001665:Binding Sites; D020746:Calcium Channels, L-Type / Q000737:chemistry / Q000378:metabolism*; D020013:Calcium Signaling; D002147:Calmodulin / Q000378:metabolism; D015687:Cell Hypoxia; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation
D020746:Calcium Channels, L-Type; D002147:Calmodulin; D017868:Cyclic AMP-Dependent Protein Kinases; D010100:Oxygen