Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are highly regulated proteins which respond to different cellular stimuli. The HCN currents (Ih) mediated by HCN1 and HCN2 drive the repetitive firing in nociceptive neurons. The role of HCN channels in pain has been widely investigated as targets for the development of new therapeutic drugs, but the comprehensive design of HCN channel modulators has been restricted due to the lack of crystallographic data. The three-dimensional structure of the human HCN1 channel was recently reported, opening new possibilities for the rational design of highly-selective HCN modulators. In this review, we discuss the structural and functional properties of HCN channels, their pharmacological inhibitors, and the potential strategies for designing new drugs to block the HCN channel function associated with pain perception.
Highlights
HCN Channels Structure and FunctionHyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated pore loop channel superfamily [1,2,3], and are related to the cyclic nucleotide-gated (CNG) channels as well as to the voltage-dependent KV 10–KV 12 channels [4] (Figure 1A)
Besides the voltage-dependent gating, HCN channels are activated by intracellular cyclic nucleotides [5,6], including guanosine-30,50 -cyclic monophosphate and adenosine-30,50 -cyclic monophosphate, while the modulation of Ih is similar for both cyclic nucleotides, with the same efficacy at least in mammalians, the apparent affinities of Ih are 10–100 fold higher for cyclic adenosine monophosphate (cAMP) than for cGMP [7]
Hyperpolarization-activated cyclic nucleotide-gated channels are integrated by four subunits that together form a central pore
Summary
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are members of the voltage-gated pore loop channel superfamily [1,2,3], and are related to the cyclic nucleotide-gated (CNG) channels as well as to the voltage-dependent KV 10–KV 12 channels [4] (Figure 1A). Hyperpolarization-activated cyclic nucleotide-gated channels are integrated by four subunits that together form a central pore. The cAMP modulation, in HCN channels, is generated by a direct binding to the intracellular cyclic nucleotide binding domain (CNBD) located at C-terminal. This binding leads to accelerated activation kinetics and to a shift of the conductance voltage curve toward positive voltages A cyclic nucleotide-binding domain (CNBD) is found at the intracellular C-terminus of HCN channels. It includes selected ion channels of Kv (voltage-gated K channel), NALCN Phylogenetic channel, non-selective), and CNG (cyclicEvolutionary nucleotide-gated ion Analysis channel) version families..
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
