Calmodulin regulation of kv7.2 potassium channels

Supervised by:
  1. Álvaro Villarroel Muñoz Director

Defence university: Universidad del País Vasco - Euskal Herriko Unibertsitatea

Fecha de defensa: 30 January 2015

  1. Alicia Alonso Izquierdo Chair
  2. Sonia Bañuelos Rodriguez Secretary
  3. Christian Wahl-Schott Committee member
  4. Antonio Felipe Campo Committee member
  5. Francisco Barros de la Roza Committee member

Type: Thesis

Teseo: 118396 DIALNET


This doctoral dissertation is an advance in our knowledge of Kv7.2 neuronal potassiumchannels and how the auxiliary protein, calmodulin, regulates their function. Calmodulin is anecessary protein for channel assembly, trafficking and gating; and mutations that disruptcalmodulin and Kv7.2 interactions lead to a kind of benign epilepsy known as BFNC. However,sometimes the pathophysiology gets more severe and they can cause encephalopathies andmental retardation. Within the first chapter of this dissertation, we study in vitro and in vivohow calmodulin binds to Kv7.2 channels, and how this interaction regulates channel traffickingto the membrane; and finally, the function. Kv7.2 channels contain two binding domainsdenoted helices A and B, and the conclusion reached is that binding to helix A is moreimportant and necessary for channel function. In the second part of results, we deal with howcalmodulin binding affects other regulatory processes of Kv7.2 channels. We describe howtetramerization and calmodulin binding are interconnected and how an epileptogenicmutation (L609R) in the assembly domain, although far from the calmodulin binding site, altersthis association. Functional characterization of the mutant shows there is an alteration onchannel activate state and that calmodulin current potentiation and PIP2 regulation are bothlost. Although the C-terminal of Kv7 channels has been envisioned as modular andindependent linked helices, the modules interact between each other and there is a tightrelationship between assembly, calmodulin binding and PIP2 regulation.