VanSchouwen Bryan, Melacini Giuseppe
Department of Chemistry and Chemical Biology, McMaster University, 1280 Main Street West, Hamilton, ON, Canada, L8S 4M1.
Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON, Canada, L8S 4M1.
Handb Exp Pharmacol. 2017;238:123-133. doi: 10.1007/164_2016_5006.
The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) proteins are cAMP-regulated ion channels that play a key role in nerve impulse transmission and heart rate modulation in neuronal and cardiac cells, respectively. Although they are regulated primarily by cAMP, other cyclic nucleotides such as cGMP, cCMP, and cUMP serve as partial agonists for the HCN2 and HCN4 isoforms. By competing with cAMP for binding, these non-canonical ligands alter ion channel gating, and in turn, modulate the cAMP-dependent activation profiles. The partial activation of non-canonical cyclic nucleotides can be rationalized by either a partial reversal of a two-state inactive/active conformational equilibrium, or by sampling of a third conformational state with partial activity. Furthermore, different mechanisms and degrees of activation have been observed upon binding of non-canonical cyclic nucleotides to HCN2 versus HCN4, suggesting that these ligands control HCN ion channels in an isoform-specific manner. While more work remains to be done to achieve a complete understanding of ion channel modulation by non-canonical cyclic nucleotides, it is already clear that such knowledge will ultimately prove invaluable in achieving a more complete understanding of ion channel signaling in vivo, as well as in the development of therapeutics designed to selectively modulate ion channel gating.
超极化激活的环核苷酸调制（HCN）蛋白是受环磷酸腺苷（cAMP）调节的离子通道，分别在神经元细胞的神经冲动传递和心脏细胞的心率调节中起关键作用。尽管它们主要受cAMP调节，但其他环核苷酸，如环磷酸鸟苷（cGMP）、环磷酸胞苷（cCMP）和环磷酸尿苷（cUMP），对HCN2和HCN4亚型起部分激动剂的作用。通过与cAMP竞争结合，这些非典型配体改变离子通道门控，进而调节cAMP依赖性激活曲线。非典型环核苷酸的部分激活可以通过两态失活/激活构象平衡的部分逆转，或者通过对具有部分活性的第三种构象状态的采样来解释。此外，已观察到非典型环核苷酸与HCN2和HCN4结合后，激活机制和程度不同，这表明这些配体以亚型特异性方式控制HCN离子通道。虽然要完全了解非典型环核苷酸对离子通道的调制仍有更多工作要做，但很明显，这些知识最终将被证明在更全面地理解体内离子通道信号传导以及开发旨在选择性调节离子通道门控的治疗方法方面具有不可估量的价值。
