Effect of beta1-integrin on the regulation of the cardiac L-type calcium channel

Integrins belong to a transmembrane receptor family and serve as bi-directional messengers between the inside and outside of cells. Previous studies indicated that integrins regulate ion channel function. In this thesis, the effect of the beta1 integrin on the biophysical and regulatory properties of the cardiac L-type voltage-dependent calcium channel (VDCC) was investigated. According to my finding, beta1 integrin signaling has no effect on L-type channel expression, basal current properties and muscarinic receptor regulation. However, beta1 integrin/ECM interactions were found to interfere with beta-adrenergic receptor (betaAR) regulation of L-type channel. Overexpression of the beta1A integrin in neonatal cardiac myocytes inhibited the L-type current response to betaAR stimulation by depressing the cAMP level. In contrast, expression of the cytoplasmic tail of beta1 integrin enhanced the response to betaAR stimulation without affecting cAMP level. Expression of the beta1 integrin cytoplasmic tail also facilitated current response to Bay K 8644, a dihydropyridine (DHP) compound that stimulates Ca2+ current through directly binding to the Ca2+ channel. Myocytes isolated from beta1 integrin gene excision mice and plated on laminin showed a significant increase in current augmentation induced by ISO when compared with control mice. Myocytes isolated from wild-type mice and plated on beta1 antibody-coated coverslips showed a significant decrease in the current response to ISO compared with cells plated on IgG-coated coverslips.; My results support this hypothesis that integrin-dependent signaling inhibits betaAR regulation of L-type Ca2+ channel through multiple mechanisms. Integrins may interfere with betaAR regulation by inhibiting cAMP-dependent protein kinase pathway. Integrins may also directly associate with the L-type Ca2+ channel and modify the regulation of the channel.