Kv Channel Interacting Proteins (KChIPs) as calcium sensors for Kv4 channels
Final Report Abstract
Ion channels are pore-forming proteins in the cell membrane. Voltage-dependent potassium (Kv) channels open and close if the membrane voltage is altered, thereby allowing a coordinated K+ current across the cell membrane. In this way, Kv channels control the electrical activity (excitation) of nerve and muscle cells. There are various Kv subfamilies (Kv1 - 12). The Kv4 subfamily is found in the cell membrane of heart muscle cells, as well as the cell body and dendritic projections of nerve cells. Kv4 channels form complexes with non-pore-forming proteins (b-subunits), the so-called Kv channel-interacting proteins (KChIPs). KChIPs belong to the neuronal calcium sensor (NCS) family of calcium (Ca2+)-binding proteins. Upon their discovery, KChIPs were ascribed the role of a "Ca2+ sensor" for Kv4 channels, based on the fact that they belong to the NCS family and specifically interact with Kv4 channels. It has been postulated that, via Ca2+ binding to the KChIPs, local cytoplasmic Ca2+ concentration fluctuations may influence Kv4 channel function and thus cell excitation. There is indeed evidence in the literature that such a role is possible. However, these studies have consistently used indirect approaches to modulate the intracellular Ca2+ concentration, leaving the actual question of whether Ca2+ binding to KChIPs directly modulates Kv4 channel function; i.e., whether the KChIPs are indeed Ca2+ sensors for Kv4 channels, unanswered. Our DFG-funded research project was aimed at answering this quesion. We invesigated the opening and closing behavior of Kv4/KChIP channel complexes electrophysiologically in a cell-free recording configuration (inside-out patch-clamp method) and applied Ca2+ at different concentrations directly to the inner side of the membrane during the measurements. Surprisingly, the findings on Ca2+- dependent modulation of Kv4 channel function via KChIPs known from the literature could not be confirmed with this technically demanding and for the first time direct experimental approach. The role of KChIPs as Ca2+ sensors for Kv4 channels must therefore be reconsidered and possibly previous experimental findings need to be reinterpreted.
Publications
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KCND2 variants associated with global developmental delay differentially impair Kv4.2 channel gating. Human Molecular Genetics, 30(23), 2300-2314.
Zhang, Yongqiang; Tachtsidis, Georgios; Schob, Claudia; Koko, Mahmoud; Hedrich, Ulrike B. S.; Lerche, Holger; Lemke, Johannes R.; van Haeringen, Arie; Ruivenkamp, Claudia; Prescott, Trine; Tveten, Kristian; Gerstner, Thorsten; Pruniski, Brianna; DiTroia, Stephanie; VanNoy, Grace E.; Rehm, Heidi L.; McLaughlin, Heather; Bolz, Hanno J.; Zechner, Ulrich ... & Bähring, Robert
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Kv channel interacting proteins as Ca2+ sensors for Kv4 channels. Dissertationsschrift Fachbereich Biologie, Fakultät für Mathematik, Informatik und Naturwissenschaften der Universität Hamburg
Tachtsidis, G.
