|Título||Increased coupled gating of L-type Ca2+ channels during hypertension and Timothy syndrome.|
|Publication Type||Journal Article|
|Year of Publication||2010|
|Autores||Navedo, MF, Cheng, EP, Yuan, C, Votaw, S, Molkentin, JD, Scott, JD, Santana, LF|
|Date Published||2010 Mar 5|
|Palabras clave||A Kinase Anchor Proteins, Animals, Calcium Channels, L-Type, Calcium Signaling, Calcium-Calmodulin-Dependent Protein Kinases, Calmodulin, Cells, Cultured, Enzyme Activation, Enzyme Activators, Fluorescence Resonance Energy Transfer, Humans, Hypertension, Ion Channel Gating, Long QT Syndrome, Membrane Potentials, Mice, Mice, Knockout, Microscopy, Confocal, Muscle, Smooth, Vascular, Mutation, Myocytes, Cardiac, Myocytes, Smooth Muscle, Patch-Clamp Techniques, Protein Kinase C-alpha, Protein Kinase Inhibitors, Protein Structure, Tertiary, Protein Transport, Rabbits, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins, Time Factors, Transfection|
RATIONALE: L-Type (Cav1.2) Ca(2+) channels are critical regulators of muscle and neural function. Although Cav1.2 channel activity varies regionally, little is known about the mechanisms underlying this heterogeneity.
OBJECTIVE: To test the hypothesis that Cav1.2 channels can gate coordinately.
METHODS AND RESULTS: We used optical and electrophysiological approaches to record Cav1.2 channel activity in cardiac, smooth muscle, and tsA-201 cells expressing Cav1.2 channels. Consistent with our hypothesis, we found that small clusters of Cav1.2 channels can open and close in tandem. Fluorescence resonance energy transfer and electrophysiological studies suggest that this coupling of Cav1.2 channels involves transient interactions between neighboring channels via their C termini. The frequency of coupled gating events increases in hypertensive smooth muscle and in cells expressing a mutant Cav1.2 channel that causes arrhythmias and autism in humans with Timothy syndrome (LQT8).
CONCLUSIONS: Coupled gating of Cav1.2 channels may represent a novel mechanism for the regulation of Ca(2+) influx and excitability in neurons, cardiac, and arterial smooth muscle under physiological and pathological conditions.
|Alternate Journal||Circ. Res.|
|PubMed Central ID||PMC2834417|
|Grant List||HL085870 / HL / NHLBI NIH HHS / United States |
HL088366 / HL / NHLBI NIH HHS / United States
HL85686 / HL / NHLBI NIH HHS / United States
R01 HL085686 / HL / NHLBI NIH HHS / United States
R01 HL085686-03 / HL / NHLBI NIH HHS / United States
R01 HL085870 / HL / NHLBI NIH HHS / United States
R01 HL085870-03 / HL / NHLBI NIH HHS / United States
R01 HL088366 / HL / NHLBI NIH HHS / United States
T32 GM007266 / GM / NIGMS NIH HHS / United States