Ask about this productRelated genes to: HCN3 antibody
- Gene:
- HCN3 NIH gene
- Name:
- hyperpolarization activated cyclic nucleotide gated potassium channel 3
- Previous symbol:
- -
- Synonyms:
- KIAA1535
- Chromosome:
- 1q22
- Locus Type:
- gene with protein product
- Date approved:
- 2002-09-02
- Date modifiied:
- 2016-10-05
Related products to: HCN3 antibody
Related articles to: HCN3 antibody
- HCN channels have a reverse electromechanical coupling mechanism, where hyperpolarized membrane potentials facilitate pore opening through an inward displacement of the S4 segment of the voltage-sensing domain (VSD). This voltage dependence is finely regulated by the binding of cAMP to an intracellular domain (CNBD). Of the four widely studied isoforms of human HCN channels, the HCN3 channel is practically insensitive to cAMP or is even inhibited by it, but the structural determinants underlying this unexpected behavior are still unclear. Here, we evaluated the possible role of flexibility in very specific regions of the VSD that could be determinants for this behavior. Part of the S2-S3L linker is more rigid in HCN3, which correlates with low atomic mobility for this region in proximity to the C-linker subdomain of the opposite subunit. We built structural models using AlphaFold 3 and Swiss-Model and thus reconstructed the disordered regions that connect the transmembrane segments of the VSD and that in some of the structures deposited in the PDB have not been resolved. Besides, in an attempt to reveal the evolutionary trends that this transmembrane domain may have undergone, we conducted a comparative study with phylogenetically distant HCN channels and found an interesting tendency to lose sensitivity to cAMP as VSD flexibility is lost. Our analysis confirms a large body of published experimental findings. Finally, we found that in metazoans, two types of HCN channels clearly diverge: (1) those that are highly sensitive to cAMP with moderate flexibility profiles in protostomes, and (2) those that show less marked sensitivity to this ligand in deuterostomes. We also propose a possible evolutionary scenario for the appearance of cAMP-modulated HCN channels in the last eukaryotic common ancestor (LECA). - Source: PubMed
Publication date: 2026/03/07
Alvarez-Villagómez Karla GBalleza Daniel - The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel HCN3 is expressed in sensory dorsal root ganglia (DRG) neurons, but its contribution to somatosensory processing remains poorly understood. Here, using RNA hybridization, we found that is widely expressed in various populations of DRG neurons. Analysis of HCN3-deficient mice in a series of behavioral tests for somatosensory function revealed that HCN3 deletion led to profound impairments in mechanical sensation on hairy skin. However, the mechanical sensation on glabrous skin and responses to noxious heat and cold stimuli were not affected in the absence of HCN3. Electrophysiological recordings revealed that deletion of HCN3 reduced the HCN current (I) density and affected the action potential kinetics in thoracic (Th9-Th10) DRG neurons, which innervate hairy skin. However, electrophysiological parameters were unaltered in lumbar (L4-L5) DRG neurons. These findings suggest that HCN3 channels are specific regulators of low-threshold mechanoreceptors that innervate hairy skin. - Source: PubMed
Publication date: 2026/01/12
Metzner KatharinaHussein-Zahovic TamaraBehery YomnaFenske StefanieBiel MartinSchmidtko Achim - The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the kidney participate in reabsorbing potassium (K) and ammonium (NH) in the nephron, contributing to the acid-base balance. Acidosis is a metabolic condition of renal tubular acidosis and chronic kidney disease. Acidosis stimulates the production of mitochondrial reactive oxygen species (mROS), activating protective mechanisms dependent on mitochondrial membrane potential (Δψm) such as autophagy. The HCN3 channel is expressed in the plasma membrane, mitochondria (mitoHCN3), and lysosomes (lysoHCN3) of the rat proximal tubule. In this work we aimed to investigate the role of HCN3 in autophagy, mROS production, and Δψm in cultured rat proximal tubule cells (NRK-52E) exposed to ammonium chloride (NHCl). NHCl arrested autophagic flux and produced extracellular acidosis and, under this condition, mitoHCN3 and lysoHCN3 were up-regulated. NHCl or/and ZD7288, a specific blocker of HCN channels, enhanced mROS. ZD7288 in NHCl conditions at 24 h stimulated autophagy by reducing Beclin1, LC3BII, p62, and Parkin in an mROS- or Δψm independent pathway. Therefore, ZD7288 reverted NHCl inhibited autophagy through lysoHCN3 inhibition. Oxidative stress induced by HO up-regulated mitoHCN3 expression, while Tiron had the opposite effect. In conclusion, inhibition of mito- and lysoHCN3 channels by ZD7288 can protect against mitochondrial oxidative stress and stimulate the lysosome-autophagy pathway in response to NHCl treatment. - Source: PubMed
Publication date: 2025/09/21
López-González ZinaeliEscobar Laura ILeón-Aparicio DanielMejía-Peralta Abirán FernandoPadilla-Flores TeresaLarre IsabelSalvador CarolinaMedina-Campos Omar NoelPedraza-Chaverri Joséde la Fuente-Granada Marisol - During GABAergic synaptic transmission, G protein-coupled GABA receptors (GBRs) activate K channels that prolong the duration of inhibitory postsynaptic potentials (IPSPs). We now show that KCTD16, an auxiliary GBR subunit, anchors hyperpolarization-activated cyclic nucleotide-gated (HCN) channels containing HCN2/HCN3 subunits to GBRs. In dopamine neurons of the VTA (DA neurons), this interaction facilitates activation of HCN channels via hyperpolarization during IPSPs, counteracting the GBR-mediated late phase of these IPSPs. Consequently, disruption of the GBR/HCN complex in KCTD16 mice leads to prolonged optogenetic inhibition of DA neuron firing. KCTD16 mice exhibit increased anxiety-like behavior in response to stress - a behavior replicated by CRISPR/Cas9-mediated KCTD16 ablation in DA neurons or by intra-VTA infusion of an HCN antagonist in wild-type mice. Our findings support that the retention of HCN channels at GABAergic synapses by GBRs in DA neurons provides a negative feedback mechanism that restricts IPSP duration and mitigates the development of anxiety. - Source: PubMed
Publication date: 2025/02/04
Pérez-Garci EnriquePysanenko KaterynaRizzi GiorgioStuder FlorianUlrich DanielFritzius ThorstenFrüh SimonPorcu AlessandraBesseyrias ValérieMelichar AdolfGassmann MartinBarkat Tania RinaldiTureček RostislavTan Kelly RBettler Bernhard - This case study investigates the role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels, which are integral membrane proteins crucial for regulating neuronal excitability. HCN channels are composed of four subunits (HCN1-4), with HCN1, HCN2, and HCN4 previously linked to epilepsy. However, the role of the HCN3 in epileptogenesis remains underexplored. - Source: PubMed
Publication date: 2024/10/03
Zhao PeiweiXiong HongboKuang GunagtaoSun ChenZhang XiankaiHuang YufengLuo SukunZhang LeiJiang JunHe Xuelian