Bibliometric analysis of hyperpolarization-activated cyclic nucleotide-gated (HCN)channels research (2004-2020)

Abstract

The HCN channel family comprises of four members (HCN1-4) expressed in the heart and nervous system. The current produced by HCN channels is known as I-h (or I-f or I-q). I-h has also been designated as pacemaker current because it plays a key role in controlling rhythmic activity of cardiac pacemaker cells and spontaneously firing neurons [1]. The diversity of functions that HCN channels perform is partly attributable to differences in their subcellular localization [2]. HCN channels are highly regulated proteins, which respond to different cellular stimuli, they open at hyperpolarizingpotential, carrymixed Na/K current, and are regulated by cyclic nucleotides [3]. These channels play important roles in modulating cellular excitability, rhythmic activity, dendritic integration, and synaptic transmission. HCN channel functions range from setting resting potential, synaptic normalization, gain control, after-hyperpolarization, setting responses in dendrites, mediating cannabinoid role in neuronal plasticity, to the gating of plasticity [4]. These functions have been implicated in a wide range of diseases, including major depressive disorder, neuropathic pain, and multiple subtypes of epilepsy [4,5. Among the four known isoforms, HCN1 is the most expressed in the neocortex and hippocampus. Some studies suggest that coordinated changes in protein expression and surface expression of HCN1 serve as the key regulatory mechanisms controlling the function of the endogenous HCN1 protein in cortical neurons [6]. HCN1 might be involved in reduced vagal modulation and possibly in increased cardiac mortality in schizophrenia patients [7]. HCN2 ion channel activity plays a crucial role in the progress of peripheral neuropathic pain (PNP). Some studies suggest that HCN2 contributes to the development of neuropathic pain by inducing spinal LTP via activation of NMDA receptor-mediated CaMKII signaling, decreased HCN2 channel expression attenuates neuropathic pain by inhibiting pro-inflammatory reactions and NF-kappa B activation[8,9] Like all other HCNs, hHCN3 was inhibited rapidly and reversibly by extracellular cesium and slowly and irreversibly by extracellular applied ZD7288. The human channel was not modulated by intracellular cAMP, a hallmark of the other known HCN channels so the missing response to cAMP distinguishes human HCN3 from both the well cAMP responding HCN subtypes 2 and 4 and the weak responding subtype 1[10]. Upregulation of HCN3 channels in IGL neurons is essential for intrinsic excitability and rhythmic burst firing, and PIP2 serves as a powerful modulator of I-h-dependent properties via an effect on HCN3 channel gating[11]. HCN4 is expressed in brain regions relevant to mood and anxiety disorders including specific thalamic nuclei, the basolateral amygdala, and the midbrain dopamine system[12].