Structure mirroring function: What's the 'matter' with the funny current?

Abstract

First described in native cardiac pacemaker cells, the 'funny' (I_f) current provided a novel mechanism able to underlie rhythmic activity and autonomic control of heart rate. Increasing the impact of this finding, the new mechanism replaced a previous pacemaking model based on a 'fake' K⁺ current (I_K2), shown in fact to be a 'camouflaged' I_f; also, a similar current in neurons (I_h) was found to regulate neuronal excitability. I_f, the first described inward current activated on hyperpolarization, had several other peculiar features, when investigated in sinoatrial node tissue and isolated cells. It had a mixed Na⁺/K⁺ permeability, had the lowest patch clamp recorded single-channel conductance, and was dually activated by voltage and intracellular cyclic nucleotides. I_f activation by internal cAMP, a property key to autonomic modulation of heart rate, was shown to involve direct cAMP binding to channels. Finally, an I_f blocking drug, ivabradine, was found to be suitable for the pharmacological control of heart rate in therapies against angina and heart failure. Later cloning of HCN channels, comprising the subunit components of funny channels, allowed molecular insight into the properties of I_f, carried by HCN4. Recently, cryogenic electron microscopy has resolved details of the HCN4 structure with unprecedented precision, providing a way to validate or refute, on a structural basis, original interpretation/modelling of experimental data. This review aims to compare elementary functional properties of I_f vs. HCN4 protein structure. Does structure 'mirror' function? We show that the peculiar I_f characteristics originally described are elegantly explained and 'mirrored' by structural features of the channel protein.