Peters Colin H, Singh Rohit K, Bankston John R, Proenza Catherine
Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Department of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
Front Physiol. 2022 Jun 20;13:928507. doi: 10.3389/fphys.2022.928507. eCollection 2022.
Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels are key regulators of subthreshold membrane potentials in excitable cells. The four mammalian HCN channel isoforms, HCN1-HCN4, are expressed throughout the body, where they contribute to diverse physiological processes including cardiac pacemaking, sleep-wakefulness cycles, memory, and somatic sensation. While all HCN channel isoforms produce currents when expressed by themselves, an emerging list of interacting proteins shape HCN channel excitability to influence the physiologically relevant output. The best studied of these regulatory proteins is the auxiliary subunit, TRIP8b, which binds to multiple sites in the C-terminus of the HCN channels to regulate expression and disrupt cAMP binding to fine-tune neuronal HCN channel excitability. Less is known about the mechanisms of action of other HCN channel interaction partners like filamin A, Src tyrosine kinase, and MinK-related peptides, which have a range of effects on HCN channel gating and expression. More recently, the inositol trisphosphate receptor-associated cGMP-kinase substrates IRAG1 and LRMP (also known as IRAG2), were discovered as specific regulators of the HCN4 isoform. This review summarizes the known protein interaction partners of HCN channels and their mechanisms of action and identifies gaps in our knowledge.
超极化激活的环核苷酸敏感（HCN）通道是可兴奋细胞阈下膜电位的关键调节因子。四种哺乳动物HCN通道亚型，即HCN1 - HCN4，在全身表达，它们参与多种生理过程，包括心脏起搏、睡眠 - 觉醒周期、记忆和躯体感觉。虽然所有HCN通道亚型单独表达时都会产生电流，但越来越多的相互作用蛋白塑造了HCN通道的兴奋性，以影响生理相关输出。这些调节蛋白中研究得最透彻的是辅助亚基TRIP8b，它与HCN通道C末端的多个位点结合，以调节表达并破坏cAMP结合，从而微调神经元HCN通道的兴奋性。对于其他HCN通道相互作用伙伴，如细丝蛋白A、Src酪氨酸激酶和MinK相关肽的作用机制了解较少，它们对HCN通道的门控和表达有一系列影响。最近，肌醇三磷酸受体相关的cGMP激酶底物IRAG1和LRMP（也称为IRAG2）被发现是HCN4亚型的特异性调节因子。本综述总结了HCN通道已知的蛋白相互作用伙伴及其作用机制，并指出了我们知识上的空白。
