Overexpression of the integrin β1A subunit and the β1A cytoplasmic domain modifies the β-adrenergic regulation of the cardiac L-type Ca2+current

Integrins are a family of cell-surface receptors that link the extracellular matrix (ECM) to the cellular cytoskeleton. The goal of this study was to determine the importance of the integrin β1 subunit in regulating cardiac L-type Ca2+ channel function. Neonatal rat ventricular myocytes were cultured on collagen membranes and infected with adenovirus expressing either the human β1A integrin (Adβ1A) or a chimeric protein consisting of the cytoplasmic tail domain of the β1A integrin and the extracellular/transmembrane domain of the interleukin-2 receptor (AdTAC-β1). Expression of the free β1 integrin tail (TAC-β1), but not the full-length β1A integrin, altered cell morphology and disrupted normal cell adhesion. When compared with myocytes infected with control virus, neither Adβ1A nor AdTAC-β1 infection produced any significant change in the current vs. voltage relationship of the whole-cell Ca2+ current (ICa) or the kinetics of ICa decay. Expression of TAC-β1, but not β1A, induced a negative shift in the Ca2+ channel steady-state inactivation curve. Application of the β-adrenergic receptor agonist isoproterenol produced over a 90% increase in ICa in control cells, but caused only an 18% increase in myocytes overexpressing the full-length β1A integrin. In addition, β-adrenergic stimulation resulted in a 5–10-fold increase in intracellular cAMP levels in control cells, but produced no significant response in Adβ1A-infected cells. In contrast, expression of TAC-β1 was associated with an augmentation in the Ca2+ channel response to isoproterenol (160% increase) and the Ca2+ channel agonist BayK8644. Thus, integrin/ECM interactions may be critical in the regulation of ICa