Role of HCN channels in the functions of basal ganglia and Parkinson's disease

Abstract

Parkinson's disease (PD) is a motor disorder resulting from dopaminergic neuron degeneration in the substantia nigra caused by age, genetics, and environment. The disease severely impacts a patient's quality of life and can even be life-threatening. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a member of the HCN1-4 gene family and is widely expressed in basal ganglia nuclei. The hyperpolarization-activated current mediated by the HCN channel has a distinct impact on neuronal excitability and rhythmic activity associated with PD pathogenesis, as it affects the firing activity, including both firing rate and firing pattern, of neurons in the basal ganglia nuclei. This review aims to comprehensively understand the characteristics of HCN channels by summarizing their regulatory role in neuronal firing activity of the basal ganglia nuclei. Furthermore, the distribution and characteristics of HCN channels in each nucleus of the basal ganglia group and their effect on PD symptoms through modulating neuronal electrical activity are discussed. Since the roles of the substantia nigra pars compacta and reticulata, as well as globus pallidus externus and internus, are distinct in the basal ganglia circuit, they are individually described. Lastly, this investigation briefly highlights that the HCN channel expressed on microglia plays a role in the pathological process of PD by affecting the neuroinflammatory response.

Keywords: Basal ganglia; Firing pattern; Firing rate; HCN channel; Hyperpolarization-activated current; Parkinson’s disease.

Fig. 1

Probable structure of HCN channels. HCN channels function as tetramers, which can be homologous or heterologous (left). Each HCN subunit comprises six transmembrane segments: the NH2 terminal, the voltage sensor (S4), the pore region between S5 and S6, and the COOH terminal (right). The pore region contains the selectivity filter that carries the glycine-tyrosine-glycine amino-acid (GYG) sequence. The channel’s COOH terminal domain comprises the C-linker (comprises six α-helices designated A’ to F’) and the cyclic nucleotide-binding domain (CNBD) located after the C-linker domain. CNBD consists of alpha-helices A–C and a beta-roll between helices A and B. TRIP8b and cAMP regulate CNBD

Fig. 2

Function of neuronal HCN channels in basal ganglia nuclei. The basal ganglia, a subcortical structure, plays a crucial role in regulating motor function by processing information from and feeding it back to the cerebral cortex. Substantia nigra, a key nucleus within the basal ganglia, functions as a regulatory agent. HCN channels, which are important in regulating the normal electrical activity of neurons, are expressed in the basal ganglia nuclei. HCN hyperpolarization-activated cyclic nucleotide-gated channel, ChIs cholinergic interneurons, d-SPNs direct pathway-striatal projection neurons, i-SPNs indirect pathway-striatal projection neurons, SNpc substantia nigra pars compacta, SNr substantia nigra pars reticulata, GPe globus pallidus externus, EPN entopeduncular nucleus, PV parvalbumin, STN subthalamic nucleus

Fig. 3

The relationship between the expression of HCN channels in the basal ganglia nuclei and the symptoms of PD. The expression of HCN channels in neurons of the basal ganglia nuclei was downregulated in the pathological state of PD. The downregulation of HCN channels in dopaminergic neurons results in decreased neuronal firing rates, which are associated with motor dysfunction. The downregulation of HCN channels in striatal ChIs results in decreased neuronal firing rates, which are associated with cognitive dysfunction. The downregulation of HCN channels in GPe/STN/SNr/EPN PV neurons results in decreased neuronal firing rates and irregularized firing pattern, which are associated with motor dysfunction. PD Parkinson’s disease, HCN hyperpolarization-activated cyclic nucleotide-gated channel, ChIs cholinergic interneurons, SNpc substantia nigra pars compacta, SNr substantia nigra pars reticulata, GPe globus pallidus externus, EPN entopeduncular nucleus, PV parvalbumin, STN subthalamic nucleus