Entropic Clocks in the Service of Electrical Signaling

Abstract

Electrical signaling in the nervous system relies on action potential generation, propagation and transmission. Such processes rely on precisely timed events associated with voltage-dependent ion channel conformational transitions between the closed, open and inactivated states, as well as clustering at unique membrane sites. In voltage-dependent potassium channel (Kv) protein, the activation, inactivation and clustering mechanisms are based on interactions involving either folded membrane-spanning domains or intrinsically disordered protein segments. While the role of the Kv channel in generating action potentials is primarily based on channel activation gating, mediated by tight electro-mechanical coupling between the channel voltage-sensing and pore domains, the regulation of action potential shape and frequency involves Kv channel inactivation and clustering, mediated by intrinsically disordered segments respectively found at the channel N- and C-termini. These IDP tails function as entropic clocks to time distinct binding events, relying on what is traditionally referred to as a ‘Ball and Chain’ mechanism. In my presentation, I will discuss the experimental criteria that argue for an entropic clock function for IDP segments and delineate the expected thermodynamic signature of this function. Using the Kv channel example, I will summarize results demonstrating that Kv channel fast inactivation and clustering occurs according to a ‘Ball and Chain’ mechanism and will provide evidence for the compatibility of the two processes, while considering their similarities and differences. Furthermore, I will present evidence for thermodynamic coupling between the inactivation and clustering functions of the Kv channel and will discuss the enigmatic question of how such coupling is even possible, considering the entropic clock-based mechanisms underlying these functions. Finally, I will address the Kv channel and IDP fields from a historic context to show how earlier efforts advanced our understanding of the role served by entropic clocks in electrical signaling.