Alejandro Akrouh

Research

I’m interested in understanding the KATP channel form-function relationship and in exploring how deviations from WT lead to a broad spectrum of disease phenotypes. I have probed a novel mutation in the Kir6.2 subunit, V290M, identified in a patient with congenital hyperinsulinism. Rubidium efflux experiments performed on COSm6 cells expressing WT, mutant, and a combination of both revealed that the mutation did in fact decrease channel activity. Previously reported mutations in KATP channels that result in loss of function are mostly associated with trafficking defects such that a loss of function is not due to any intrinsic channel property but rather to a lack of cell-surface channel density. Interestingly, the V290M mutation does not alter trafficking. Patch-clamp experiments revealed rapid current decay upon patch excision, suggesting inactivation as the cause for decreased activity. Valine 290 is located adjacent to an intersubunit salt bridge which is essential for channel function. The V290M mutation may be disrupting this salt bridge, leading to a destabilization of the channel pore, elegantly explaining the resultant inactivation. Future efforts will go towards modeling KATP channel inactivation with the goal of refining current kinetic schemes for channel gating.

I am also involved in several projects including mapping of spermine pore biding site, identifying and exploring the differential pharmacology of SUR1 vs. SUR2a, and FRET analysis of channel structure and assembly.