LIAISON: Molecular mechanisms and pathophysiological importance of a novel interaction between Kv channels across families

• Applicants: Dr. Moritz Lindner; Dr. Vijayaram Kumar Renigunta, Ph.D.
• Subject Area: Anatomy and Physiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 462553191

Voltage-gated K+ (Kv) channels usually are formed by tetrameric assembly of four related family members to allow for K+ flux over the plasma membrane in response to depolarization of the membrane potential. The Kv5, Kv6, Kv8 and Kv9 families are particular, as they are electrically silent (termed silent Kv, “KvS”), when expressed alone. However, they co assemble with Kv2 subunits into heteromers with properties differing from those of homomeric Kv2 channels. This Kv2-KvS co-assembly constitutes the only yet known example for heteromerization of subunits across Kv families. We recognised that Kv7 subunits exhibit higher homology to KvS than to all other families and wondered whether – in analogy to Kv2 – Kv7 channels might also be modulated by KvS. In extensive pilot experiments, we indeed found that KvS modulated activity, biophysical properties, and plasma membrane expression of recombinant Kv7 isoforms in a subunit-specific manner. We also acquired evidence for co-localization of KvS and Kv7 subunits in a common protein complex, which may enable direct interaction and potentially even heteromerization of these subunits. We furthermore found that Kv7 and Kv8 (the only KvS with established disease relevance) are co-expressed in hippocampal neurons and retinal photoreceptors. As mutations in Kv7 and Kv8 subunits appear to cause similar pathologies (e.g. epilepsy and sensory impairment), these findings indicate potential (patho)physiological relevance of the Kv7-KvS interaction. Indeed, pathogenic Kv8 mutations attenuated Kv7 currents in a way that may contribute to development of Kv8-related epilepsy and a retinopathy. We propose LIAISON, a joint research effort of three laboratories with complementary expertise to unravel the mechanisms and implications of the unexpected interaction between Kv7 and KvS subunits. We will utilize a combination of biochemical, electrophysiological and imaging techniques to elucidate the molecular mechanisms and principles of the interaction in expression systems, and we will identify the protein motifs that allow for KvS-dependent modulation of Kv7 currents. We will also explore whether the principles identified in recombinant systems apply in native tissue and thereby unravel the physiological relevance of Kv7-KvS complexes in hippocampus and retina. Eventually, we will establish treatment options for a Kv8-related disorder by repurposing Kv7 channel agonists and by exploring gene-therapeutic strategies. In summary, LIAISON will deliver significant insight into the molecular principles underlying a novel interaction between members of different Kv channel families, thereby challenging a central theorem on the formation of functional Kv channels. Our project will provide new insight into the heterogeneity of native Kv channel complexes and offers novel treatment perspectives against Kv-dependent channelopathies.

• DFG Programme: Research Grants
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Cooperation Partners: Dr. Kai Kummer; Dr. Michael Leitner