beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway.
Voltage-dependent calcium channels (VDCCs) play a pivotal role in normal excitation-contraction coupling in cardiac myocytes. These channels can be modulated through activation of beta-adrenergic receptors (beta-ARs), which leads to an increase in calcium current (I(Ca-L)) density through cardiac Ca(v)1 channels as a result of phosphorylation by cAMP-dependent protein kinase A. Changes in I(Ca-L) density and kinetics in heart failure often occur in the absence of changes in Ca(v)1 channel expression, arguing for the importance of post-translational modification of these channels in heart disease. The precise molecular mechanisms that govern the regulation of VDCCs and their cell surface localization remain unknown. Our data show that sustained beta-AR activation induces internalization of a cardiac macromolecular complex involving VDCC and beta-arrestin 1 (beta-Arr1) into clathrin-coated vesicles. Pretreatment of myocytes with pertussis toxin prevents the internalization of VDCCs, suggesting that G(i/o) mediates this response. A peptide that selectively disrupts the interaction between Ca(V)1.2 and beta-Arr1 and tyrosine kinase inhibitors readily prevent agonist-induced VDCC internalization. These observations suggest that VDCC trafficking is mediated by G protein switching to G(i) of the beta-AR, which plays a prominent role in various cardiac pathologies associated with a hyperadrenergic state, such as hypertrophy and heart failure.
Lipsky
Rachele
R
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Potts
Essie M
EM
Tarzami
Sima T
ST
Puckerin
Akil A
AA
Stocks
Joanne
J
Schecter
Alison D
AD
Sobie
Eric A
EA
Akar
Fadi G
FG
Diversé-Pierluissi
María A
MA
D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D002966:Clathrin / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D032342:Muscle Cells / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013379:Substrate Specificity; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605256:Arrb1 protein, rat; D019390:Arrestins; D020746:Calcium Channels, L-Type; D002966:Clathrin; C419385:L-type calcium channel alpha(1C); D010455:Peptides; D011943:Receptors, Adrenergic, beta; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D017868:Cyclic AMP-Dependent Protein Kinases