Changing a Dogma in Ion Channel Function

LIAISON

A Multidisciplinary Research Project to Question a Dogma on the Functionality of Ion Channels

Voltage-gated potassium (K_v) channels are a diverse group of proteins that allow for flux of K⁺ ions across biological membranes in response to membrane potential depolarization. Their function is essential for a plethora of cellular processes including the determination of neuronal excitability and action potential firing, the fine-tuning of K⁺ homeostasis, regulation of cell growth and division and to maintain the physiology of sensory cells such as photoreceptor in the retina or auditory hair cells. The relevance of these proteins is highlighted by the fact that loss-of-function of K_v channels causes hereditary epilepsy, deafness and blindness to mention only few prominent diseases.

Functional K_v channels co-assemble as tetramers of four α-subunits that are arranged around the central ion conducting pore. Based on sequence homology, K_v channels have been classified into twelve families (K_v1-K_v12), and it is widely accepted that functional K_v channel tetramers are usually formed by four identical subunits (homomeric channels) or closely-related family members (heteromeric channels).

Within the large number of K_v channels, the ten members of the K_v5, K_v6, K_v8 and K_v9 families are striking exceptions: They do not form functional channels, when expressed alone, and hence where termed electrically silent K_v channels (K_vS). However, K_vS heteromerize with K_v2 channels to modulate their channel function. This constitutes the only yet accepted functional co-assembly of K_v subunits into functional K_v channels.

In extensive preliminary studies, we found that co-assembly of K_v subunits between families is not restricted to K_vS-K_v2, but also extends to other patho-physiologically-highly relevant K_v family. We thus hypothesise that K_v channels -in respect of co-assembly into functional ion channels- are more promiscuous than previously anticipated and that this novel interaction between K_v channel families is pathophysiologically relevant and causes several diseases.

To elaborate these hypotheses, we teamed-up into an international collaborative research initiative termed LIASION that brings together for young scientists at the Institute of Physiology at Medical University of Innsbruck (Austria; PD Dr. Michael Leitner and Kai Kummer, PhD) and the Institute of Physiology at Philipps-University in Marburg (Germany; Dr. Vijay Renigunta and Dr. Moritz Lindner). We have a long-standing expertise in analysis of K⁺ channels employing a complementary spectrum of experimental techniques to comprehensively analyse the physiological relevance of ion channels from molecule to behaviour and pathophysiology.

We now join forces in LIASION to question a central neurophysiological dogma on the functional co-assembly of voltage-gated K+ channels.

LIAISON brings together experts on ion channel research combining a complementary set of methods that will be combined to question a central dogma on the co-assembly of functional K_v channels.

We will analyse the mechanisms and pathophysiological relevance of this novel interaction in recombinant systems in neurons and in the retina.