Caveolin-1 Inhibits Vascular KATP Channels by Modulating Channel Sensitivity to MgADP

Caveolae are small vesicular invaginations of the plasma membrane enriched in cholesterol, sphingolipids and the cholesterol-binding protein, caveolin [1]. Aside from roles in caveolae formation and stability, caveolins interact with many caveolae-localised molecules via an N-terminal region known as the caveolin scaffolding domain. One of the many signalling proteins that reside in caveolae and interact with caveolins is the vascular ATP-sensitive potassium (KATP) channel [2], an ion channel important in the control of smooth muscle contractility and so blood flow. Here we investigate the potential role of caveolin in regulating KATP channel behaviour.Pinacidil-evoked recombinant whole-cell KATP (Kir6.1/SUR2B) currents recorded in HEK293 cells stably expressing caveolin-1 (69.6 ± 8.3pA/pF, n=8) were found to be significantly smaller than currents recorded in caveolin-null cells (179.7 ± 35.9pA/pF, n=6; p<0.05), indicating that interaction with caveolin-1 may inhibit channel activity. The addition of a peptide corresponding to the caveolin-1 scaffolding domain to the pipette-filling solution had a similar inhibitory effect on whole-cell recombinant KATP currents. In cell-attached patch clamp recordings, the presence of caveolin-1 significantly reduced channel open probability and the amount of time spent in a relatively long-lived open state. Sensitivity of the channel to its physiological regulator MgADP was significantly altered by caveolin-1 and can explain these changes in channel kinetic behaviour.Our findings suggest that interaction with caveolin-1 has an inhibitory effect on arterial-type KATP channel activity that may be important in both the physiological and pathophysiological control of vascular function.1. Parton & Simons (2007). Nat Rev Mol Cell Biol8, 185-194.2. Sampson et al. (2004). Circ Res95, 1012-1018.Supported by the BBSRC and the BHF