3otf | pdb_00003otf
Structural basis for the cAMP-dependent gating in human HCN4 channel
Structural highlights
Disease[HCN4_HUMAN] Sick sinus syndrome;Brugada syndrome. Sick sinus syndrome 2 (SSS2) [MIM:163800]: The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS2 onset is in utero or at birth. Note=The disease is caused by mutations affecting the gene represented in this entry.[1] [2] Brugada syndrome 8 (BRGDA8) [MIM:613123]: A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. Note=The disease is caused by mutations affecting the gene represented in this entry.[3] Function[HCN4_HUMAN] Hyperpolarization-activated ion channel with very slow activation and inactivation exhibiting weak selectivity for potassium over sodium ions. May contribute to the native pacemaker currents in heart (If) and in neurons (Ih). Activated by cAMP. May mediate responses to sour stimuli.[4] [5] Publication Abstract from PubMedHyperpolarization-activated cAMP-regulated (HCN) channels play important physiological roles in both cardiovascular and central nervous systems. Among the four HCN isoforms, HCN2 and HCN4 show high expression levels in the human heart, with HCN4 being the major cardiac isoform. Previously published crystal structure of mouse HCN2 (mHCN2) C-terminal fragment, including the C-linker and the cyclic-nucleotide binding domain (CNBD), has provided many insights into the cAMP-dependent gating in HCN channels. However, structures of other mammalian HCN channel isoforms have been lacking. Here we used a combination of approaches including structural biology, biochemistry, and electrophysiology, to study the cAMP-dependent gating in HCN4 channels. First we solved the crystal structure of the C-terminal fragment of human HCN4 (hHCN4) channel at 2.4A. Overall we observed a high similarity between mHCN2 and hHCN4 crystal structures. Functional comparison between two isoforms revealed that compared to mHCN2, the hHCN4 protein exhibited marked different contributions to channel function, such as an approximately 3-fold reduction in the response to cAMP. Guided by the structural differences in the loop region between beta4 and beta5 strands, we identified residues that could be partially accounted for the differences in the response to cAMP between mHCN2 and hHCN4 proteins. Moreover, upon cAMP binding, hHCN4 C-terminal protein exerts a much prolonged effect in channel deactivation which could have significant physiological contributions. Structural basis for the camp-dependent gating in human HCN4 channel.,Xu X, Vysotskaya ZV, Liu Q, Zhou L J Biol Chem. 2010 Sep 9. PMID:20829353[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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