Elsevier

Progress in Neurobiology

Volume 112, January 2014, Pages 1-23
Progress in Neurobiology

Neurophysiology of HCN channels: From cellular functions to multiple regulations

https://doi.org/10.1016/j.pneurobio.2013.10.001Get rights and content

Highlights

  • ā€¢

    Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are involved in multiple physiological processes.

  • ā€¢

    HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli.

  • ā€¢

    Dysregulation of HCN channels is involved in a variety of neurological disorders.

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels are encoded by HCN1-4 gene family and have four subtypes. These channels are activated upon hyperpolarization of membrane potential and conduct an inward, excitatory current Ih in the nervous system. Ih acts as pacemaker current to initiate rhythmic firing, dampen dendritic excitability and regulate presynaptic neurotransmitter release. This review summarizes recent insights into the cellular functions of Ih and associated behavior such as learning and memory, sleep and arousal. HCN channels are excellent targets of various cellular signals to finely regulate neuronal responses to external stimuli. Numerous mechanisms, including transcriptional control, trafficking, as well as channel assembly and modiļ¬cation, underlie HCN channel regulation. In the next section, we discuss how the intracellular signals, especially recent findings concerning protein kinases and interacting proteins such as cGKII, Ca2+/CaMKII and TRIP8b, regulate function and expression of HCN channels, and subsequently provide an overview of the effects of neurotransmitters on HCN channels and their corresponding intracellular mechanisms. We also discuss the dysregulation of HCN channels in pathological conditions. Finally, insight into future directions in this exciting area of ion channel research is provided.

Introduction

The hyperpolarization-activated current, Ih, was first observed in sino-atrial node tissue in 1976 and later was identified in rod photoreceptors and hippocampal pyramidal neurons (Bader et al., 1979, Halliwell and Adams, 1982, Noma and Irisawa, 1976). Due to its unique properties, particularly the activation upon hyperpolarization of the membrane potential, Ih has been also termed If (f for funny) or Iq (q for queer). The hyperpolarization-activated cyclic nucleotide-gated (HCN) cation ion channels underlying Ih were discovered in the late 1990s and subsequently, the genes encoding these channels were identified, which enable the expression of HCN channels in heterologous systems (Ludwig et al., 1998, Ludwig et al., 1999, Santoro et al., 1998, Seifert et al., 1999).

Unlike most other voltage-gated channels, the activation of HCN channels is controlled through dually interdependent membrane potentials and cAMP binding (Kusch et al., 2010, Wu et al., 2011). HCN channels are activated upon hyperpolarization of the membrane potential with sigmoidal kinetics, and this process is facilitated through cAMP, which directly interacts with the channel proteins. These channels do not exhibit voltage-dependent inactivation, and opening HCN channel allows the permeability of K+ and Na+ ions for the generation of the inward current Ih in the nervous system (Biel et al., 2009, Wahl-Schott and Biel, 2009). Ih contributes to diverse neuronal functions, including the determination of resting membrane potential (RMP), generation of neuronal oscillation, and regulation of dendritic integration and synaptic transmission, and is implicated in multiple physiological processes, such as sleep and arousal, learning and memory, and sensation and perception. In the nervous system, the functional properties and expression of HCN channels are diversified to adapt to the corresponding physiological roles, due to the dynamic and precise regulation of these channels through a wide range of cellular signals. The regulation of HCN channels involves short-term regulation through cellular metabolites that directly interact with these channels or protein kinases that induce phosphorylation of channel proteins, and long-term regulation via the regulation of channel expression, heteromerization or subcellular redistribution.

In this review, we provide a brief up-to-date summary of the biophysical properties, structure and distribution patterns of HCN channels in the nervous system. These aspects of HCN channels have been well reviewed, and more detailed information can be obtained from several excellent prior publications (Wahl-Schott and Biel, 2009, Robinson and Siegelbaum, 2003, Postea and Biel, 2011). Accordingly, we focus on the recent insights into the effects of Ih on membrane properties, the associated physiological functions, and regulation mechanisms underlying HCN channels. Finally, we provide an overview of the dysfunction of HCN channels and corresponding cellular mechanisms in pathological conditions with the goal of identifying the role of dysregulated HCN channels in the pathogenesis of several diseases.

Section snippets

Structure and distribution of HCN channels

HCN channels belong to the superfamily of voltage-gated pore loop channels with four pore-forming subunits (HCN1-4) encoded by the HCN1-4 gene family in mammals (Robinson and Siegelbaum, 2003). Each subunit has six transmembrane helices (S1ā€“S6), with the positively charged voltage sensor (S4) and the pore region carrying the GYG motif between S5 and S6, which forms the ion selectivity filter (Macri et al., 2012). Following S6 is the 80-residue C-linker comprising six Ī±-helices (Aā€²ā€“Fā€²) and the

The effects of Ih on membrane properties and associated physiological functions

As HCN channels are activated at membrane potentials more negative to āˆ’50Ā mV, a small fraction of HCN channels tonically open at RMP. This inward current exerts two effects on the membrane. First, tonic Ih reduces the membrane input resistance, potentially suppressing membrane potential fluctuations to a given current stimulus, dampening dendritic integration and reducing synaptic-driving neuronal excitability. Second, inward Ih depolarizes the membrane and brings the membrane potential closer

The modulation of HCN channels by intracellular molecules

As summarized above, Ih is involved in many physiological processes. The normal functions of HCN channels are highly dependent on the dynamic neurochemical environment, and these channels are excellent targets of broad cellular signals to finely regulate neuronal responses to external stimuli (Wang et al., 2011, Wang et al., 2007). Many intracellular molecules, including small molecules (e.g. cAMP, PIP2, protons), protein kinases (e.g. Src, p38-MAPK, PKC, cGKII, Ca2+/CaMKII) and interacting

Dysregulation of HCN channels is involved in pathological conditions

An important role for Ih has been implicated in many physiological activities and in the regulation of neuronal intrinsic excitability and synaptic transmission. To adapt to the functional requirements, Ih is strongly and dynamically modulated according to physiological conditions or different developmental stages. An altered function or expression of HCN channels in the nervous system might lead to pathological conditions (Table 2) (Lewis and Chetkovich, 2011).

Future perspectives

In the past decades, the structure, functional roles and modulation of HCN channels have been extensively studied using modeling approaches, X-ray crystallography, biochemistry and genetic animal models. Although numerous questions remain unsettled, as mentioned in some excellent reviews (Biel et al., 2009, Wahl-Schott and Biel, 2009), recent studies have attempted to provide reasonable explanations. Speciļ¬cally, based on the huge amount of data, a general picture has emerged for understanding

Acknowledgments

The authors acknowledge Prof. Xiongli Yang in Fudan University, Shanghai, China for advice and comments on this manuscript. We also appreciate Quanhui Chen and Jingcheng Li in the Third Military Medical University, Chongqing, China for their help in making the tables in this manuscript. This work was funded by grants from the National Natural Science Foundation of China (NO. 31000490).

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