Molecular Determinants and Functional Consequences of Pannexin Mechanosensitivity

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Pannexins are channel forming glycoproteins that conduct robust macroscopic currents across the plasma membrane, allowing flux of organic and inorganic cations and anions of up to 1 kDa in size, including ATP. Amongst the three known isoforms (Panx1-3) Panx1 has long been viewed as the predominant functional subtype and has been linked to physiological processes including astrocytic calcium wave propagation and forms of synaptic plasticity underlying learning and memory. Despite progress in identifying physiological functions contributed by Panx1, our understanding of mechanisms that promote their activation is rudimentary. The absence of fundamental knowledge regarding Panx1 gating mechanisms is a barrier to furthering our understanding of the biological functions executed by these channels. Intriguingly, Panx1 channels are known to respond to mechanical stimulus. However, the mechanisms underlying Panx1 mechanosensitivity are not known. Past studies suggest that coupling of mechanosensitive channels to cytoskeletal components, such as actin and microtubules, is a leitmotif for channel-mediated transduction of mechanical stimuli into cellular responses. Of note, the carboxyl terminus of Panx1 has been shown to interact with filamentous actin (F-actin). However, the functional consequence of this interaction has not been determined. Using a combination of molecular, biochemical, electrophysiological and super-resolution imaging approaches, work to be undertaken by HQPs in my lab will seek to identify the molecular mechanisms responsible for Panx1 mechanosensitivity and the contribution of Panx1 mechanosensitivity to cell motility and cellular adaptations to mechanical stimuli. Given increasing recognition and interest in identifying mechanisms that allow cells to sense and respond to changes in the mechanical properties in their environment, the proposed experiments will provide important insight regarding the contribution of Panx1 to mechanobiology.