Control of HCN channel gating and physiology by newly identified interaction partners

• Applicant: Dr. Gerd Zolles
• Subject Area: Anatomy and Physiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566211124

HCN channels are non-specific cation channels activated by hyperpolarization of the membrane potential and modulated by intracellular nucleotides (cAMP). In the mammalian brain, they are involved in a variety of physiological processes such as pacemaker function, dendritic integration of postsynaptic potentials, regulation of neuronal excitability, resonance phenomena and memory. These very different processes require channels with properties adapted to the specific conditions and tasks. Like other ion channels, HCN channels are macromolecular protein complexes composed of pore-forming and associated proteins, that modulate and control the biophysical properties of the channels, allowing them to be optimally adapted to the required functions. In recent proteomic analyses of native HCN channels from mouse brain, we identified two previously unknown proteins, HCN-ip1 and 2, in addition to the established channel subunits. First studies in heterologous expression systems (epithelial cells, Xenopus oocytes) showed that the association of these proteins significantly modifies the biophysical properties of HCN channels: The voltage dependence of activation is shifted by 30-40 mV to more negative membrane potentials, and this effect on channel gating is controlled by cAMP and G-protein coupled receptors (GPCRs). The considerable magnitude of their effect, as well as their modulability by cellular signaling pathways, predestine the HCN-ip1, 2 proteins to significantly expand the bandwidth of HCN channels with different properties adapted to the respective requirements. Proteomic, biochemical and electrophysiological experiments will be used to elucidate the molecular basis of the action of HCN-ip 1 and 2 and to investigate their significance for signaling in the rodent brain. It is expected that the planned investigations will both contribute to the reinterpretation of known HCN channel-dependent processes and lead to the identification of novel functions of these channels.

• DFG Programme: Research Grants