Coordinated regulation of vascular Ca2+ and K+ channels by integrin signaling

Abstract

A role for integrins in mechanotransduction has been suggested because these molecules form an important mechanical link between the extracellular matrix (ECM) and the cytoskeleton. An example of mechanotransduction in blood vessels is the myogenic response--the rapid and maintained constriction of arterioles in response to pressure elevation. L-type calcium channels and large-conductance, calcium-activated potassium (BK) channels are known to play important roles in the myogenic response and in the maintenance of myogenic (pressure-induced) vascular tone. Our recent studies on isolated, cannulated arterioles and freshly-dispersed arteriolar smooth muscle cells show that both L-type calcium channels (Ca(v)1.2) and BK channels are regulated by alpha5beta1 integrin activation. Alpha5beta1 integrin interacts with the ECM protein fibronectin, which is distributed in basement membrane and interstitial matrices surrounding smooth muscle cells within the arteriolar wall. Truncation and site-directed mutagenesis strategies reveal that regulation of Ca(v)1.2 by alpha5beta1 integrin requires phosphorylation of the channel alpha1C subunit at C-terminal residues Ser-1901 and Tyr-2122. Likewise, BK channel potentiation by alpha5beta1 integrin activation requires c-Src phosphorylation of the channel alpha-subunit at residue Tyr-766. Thus, both L-type calcium channels and BK channels can be regulated coordinately through integrin-linked phosphorylation cascades involving c-Src. We propose that these two channels are under constitutive control by alpha5beta1 integrin-fibronectin interactions in the vessel wall such that the balance of their activity determines myogenic tone and the vascular response to vessel wall injury/remodeling.