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hyperpolarization activated cyclic nucleotide-gated potassium channel 4
Hcn4 : hyperpolarization activated cyclic nucleotide-gated potassium channel 4
A missense mutation (S672R) on the exon 7 in hHCN4 gene induces the production of an isoform of the pacemaker channel changed at cAMP binding site level: this was responsible for a familial form of an asymptomatic bradycardia.
A mutation in the exon 5 of the HCN4 gene is functionally related to a truncated protein, unable to bind cAMP and, therefore, presenting a dominant negative effect on channel function. 
CARTOON REPRESENTATION OF HCN CHANNEL TOPOLOGY
One of the four subunits is depicted here. A subunit is composed of six transmembrane domains (S1–S6). S4, the putative voltage sensor, is characterized in all four HCN subunits by the presence of 11 basic residues (2 lysines, 7 arginines, and 2 histidines) within its domain and in the close vicinity. Also drawn are the domains involved in cyclic nucleotide binding (CNBD) in the C-terminus and the cAMP molecule.
Expression of HCN1 in CNS
HCN4 is strongly expressed in the thalamic nuclei and the olfactory bulb 
Missense mutations on the exon 5 of the HCN4 gene have been found in a Japanese family suffering from sick sinus syndrome, recurrent syncopes, severe bradycardia (39 bpm), long QT interval and polymorphic ventricular tachycardia 
FUNCTION BY KNOCK-OUT
Recently a knock-out HCN mice model was developed in order to study the influence of the HCN4 isoform in pacemaker generation and rate control. It demonstrated a severe bradycardia (about 50% respect of original rate) and atrio-ventricular block in a mouse model in which HCN4 was ablated. Furthermore, a 70% in If-current was outlined in the same models with an overall reduction of the spontaneous rate of about 60%. These results confirmed the essential role of HCN4 in adult mice in controlling the impulse generation and conduction of heart impulse 
Embryonic mice carrying this deletion died between embryonic days 9.5 and 11.5 due to lack of cardiac pacemaking. In this respect, it is relevant to note that cardiac development is complete at about the same time indicating that the lack of HCN4-dependent pacemaking is incompatible with a correct cardiogenesis and with embry- odic survival 
 HCN4 (Model ID = 12)
Editor : Admin.
Contributors : Rajnish Ranjan, Michael Schartner, Nitin Khanna
To cite : [Editor], [Contributors]. Accessed on [Date] Channelpedia , http://channelpedia.epfl.ch/ionchannels/64