Mechanistic basis of pannexin channel mechanosensitivity

Abstract

Pannexin1 (Panx1) forms membrane bound mechanosensitive ion channels and forms an integral component of various physiological and patho-physiological processes. It is well established that Panx1 responds to a wide range of mechanical stimuli. However, the mechanisms governing the mechanosensitivity are not known. My thesis investigates the mechanistic basis of Panx1 mechanosensitivity by employing whole cell voltage-clamp electrophysiology, along with biochemical, molecular and imaging techniques. The results demonstrate that the filamentous actin network regulates the (i) basal channel activity of Panx1 under iso-osmotic condition, (ii) augmentation of channel activity under the hypo-osmotic condition, and (iii) inhibition of channel activity under hyper-osmotic condition. Panx1 mechanosensitive responses are inhibited in cells expressing sequentially truncated Panx1 CT (356-414), suggesting that the Panx1 mechanosensitivity is conferred by the distal CT region. Data suggests that F-actin regulates Panx1 mechanosensitivity via interaction with distal Paxn1 CT using tethered mechanisms.