{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T14:12:16Z","timestamp":1791209536237,"version":"4.1.0"},"reference-count":57,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T00:00:00Z","timestamp":1422489600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Since 2003, several loss-of-function mutations in the HCN4 gene, which encodes the HCN4 protein, have been associated with sinus node dysfunction. In  human sinoatrial node (SAN), HCN4 is the most abundant of the four isoforms of the  HCN family. Tetramers of HCN subunits constitute the ion channels that conduct the hyperpolarization-activated \u201cfunny\u201d current (If), which plays an important modulating role in SAN pacemaker activity. Voltage-clamp experiments on HCN4 channels expressed in COS-7, CHO and HEK-293 cells, as well as in Xenopus oocytes have revealed changes in the expression and kinetics of mutant channels, but the extent to which especially the  kinetic changes would affect If flowing during a human SAN action potential often  remains unresolved. In our contribution to the Topical Collection on Human Single Nucleotide Polymorphisms and Disease Diagnostics, we provide an updated review of the mutation-induced changes in the expression and kinetics of HCN4 channels and provide an overview of their effects on If during the time course of a human SAN action potential,  as assessed in simulated action potential clamp experiments. Future research may solve apparent inconsistencies between data from clinical studies and data from in vitro and  in silico experiments.<\/jats:p>","DOI":"10.3390\/ijms16023071","type":"journal-article","created":{"date-parts":[[2015,1,29]],"date-time":"2015-01-29T10:10:02Z","timestamp":1422526202000},"page":"3071-3094","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":98,"title":["Pacemaker Activity of the Human Sinoatrial Node:  An Update on the Effects of Mutations in HCN4 on the  Hyperpolarization-Activated Current"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-834X","authenticated-orcid":false,"given":"Arie","family":"Verkerk","sequence":"first","affiliation":[{"name":"Department of Anatomy, Embryology and Physiology, Academic Medical Center,  University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1340-0869","authenticated-orcid":false,"given":"Ronald","family":"Wilders","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Embryology and Physiology, Academic Medical Center,  University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2015,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1146\/annurev.me.30.020179.000515","article-title":"Sick sinus syndrome","volume":"30","author":"Bigger","year":"1979","journal-title":"Annu. Rev. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1537","DOI":"10.1172\/JCI200316387","article-title":"Pacemaker channel dysfunction in a patient with sinus node disease","volume":"111","author":"Neu","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.tcm.2003.09.006","article-title":"Pacemaker channels and sinus node arrhythmia","volume":"14","author":"Stieber","year":"2004","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.ijcard.2008.12.196","article-title":"Pacemaker activity of the human sinoatrial node: Role of the hyperpolarization-activated current, If","volume":"132","author":"Verkerk","year":"2009","journal-title":"Int. J. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1111\/j.1540-8159.2009.02563.x","article-title":"The contribution of HCN4 to normal sinus node function in humans and animal models","volume":"33","author":"Nof","year":"2010","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/s00424-010-0810-8","article-title":"HCN-related channelopathies","volume":"460","author":"Baruscotti","year":"2010","journal-title":"Pfl\u00fcg. Arch."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4117","DOI":"10.1113\/jphysiol.2013.253765","article-title":"Funny channel gene mutations associated with arrhythmias","volume":"591","author":"DiFrancesco","year":"2013","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pneurobio.2013.10.001","article-title":"Neurophysiology of HCN channels: From cellular functions to multiple regulations","volume":"112","author":"He","year":"2014","journal-title":"Prog. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1113\/jphysiol.2013.270058","article-title":"Cortical HCN channels: Function, trafficking and plasticity","volume":"592","author":"Shah","year":"2014","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3390\/ijms16011429","article-title":"HCN channels\u2014Modulators of cardiac and neuronal excitability","volume":"16","author":"Herrmann","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1562","DOI":"10.1161\/CIRCULATIONAHA.108.804369","article-title":"Molecular architecture of the human sinus node: Insights into the function of the cardiac pacemaker","volume":"119","author":"Chandler","year":"2009","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/ng.2610","article-title":"Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders","volume":"45","author":"Eijgelsheim","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3775","DOI":"10.1038\/ncomms4775","article-title":"Exercise training reduces resting heart rate via downregulation of the funny channel HCN4","volume":"5","author":"Bucchi","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.cardiores.2005.02.011","article-title":"Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model","volume":"66","author":"Zicha","year":"2005","journal-title":"Cardiovasc. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00395-007-0660-5","article-title":"Age-related down-regulation of HCN channels in rat sinoatrial node","volume":"102","author":"Huang","year":"2007","journal-title":"Basic Res. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1038\/ng.2261","article-title":"Meta-analysis identifies six new susceptibility loci for atrial fibrillation","volume":"44","author":"Ellinor","year":"2012","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2585","DOI":"10.1161\/CIRCULATIONAHA.113.003712","article-title":"Sick sinus syndrome in HCN1-deficient mice","volume":"128","author":"Fenske","year":"2013","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1093\/emboj\/cdg032","article-title":"Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2","volume":"22","author":"Ludwig","year":"2003","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27194","DOI":"10.1074\/jbc.M311953200","article-title":"Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia","volume":"279","author":"Ueda","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1056\/NEJMoa052475","article-title":"Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel","volume":"354","author":"Milanesi","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1161\/CIRCULATIONAHA.107.706887","article-title":"Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia","volume":"116","author":"Nof","year":"2007","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1161\/CIRCEP.110.949768","article-title":"cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control","volume":"3","author":"Schweizer","year":"2010","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1111\/j.1540-8167.2010.01844.x","article-title":"A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews","volume":"21","author":"Glikson","year":"2010","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2768","DOI":"10.1093\/eurheartj\/ehs391","article-title":"Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation","volume":"34","author":"Duhme","year":"2013","journal-title":"Eur. Heart J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1253\/circj.CJ-13-0996","article-title":"A novel HCN4 mutation, G1097W, is associated with atrioventricular block","volume":"78","author":"Zhou","year":"2014","journal-title":"Circ. J."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.hrthm.2014.03.002","article-title":"A novel trafficking-defective HCN4 mutation is associated with early-onset atrial fibrillation","volume":"11","author":"Macri","year":"2014","journal-title":"Heart Rhythm"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.jacc.2014.05.045","article-title":"HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy","volume":"64","author":"Milano","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/j.jacc.2014.06.1155","article-title":"The symptom complex of familial sinus node dysfunction and myocardial noncompaction is associated with mutations in the HCN4 channel","volume":"64","author":"Schweizer","year":"2014","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1111\/jce.12163","article-title":"An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia","volume":"24","author":"Nawathe","year":"2013","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1093\/europace\/eut348","article-title":"Pacemaker activity of the human sinoatrial node: Effects of HCN4 mutations on the hyperpolarization-activated current","volume":"16","author":"Verkerk","year":"2014","journal-title":"Europace"},{"key":"ref_31","first-page":"224","article-title":"Functional characterization of novel HCN4 mutations associated with cardiac arrhythmia","volume":"210","author":"Moeller","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/jhg.2008.16","article-title":"Role of HCN4 channel in preventing ventricular arrhythmia","volume":"54","author":"Ueda","year":"2009","journal-title":"J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.1016\/j.humpath.2013.01.024","article-title":"Postmortem review and genetic analysis in sudden infant death syndrome: An 11-year review","volume":"44","author":"Evans","year":"2013","journal-title":"Hum. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.1159\/000343314","article-title":"The HCN4 channel mutation D553N associated with bradycardia has a C-linker mediated gating defect","volume":"30","author":"Netter","year":"2012","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_35","first-page":"215","article-title":"Cardiac calcium channels expressed in Xenopus oocytes are modulated by dephosphorylation but not by cAMP-dependent phosphorylation","volume":"2","author":"Lotan","year":"1994","journal-title":"Recept. Channels"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2116","DOI":"10.1016\/j.str.2012.09.017","article-title":"Local and global interpretations of a disease-causing mutation near the ligand entry path in hyperpolarization-activated cAMP-gated channel","volume":"20","author":"Xu","year":"2012","journal-title":"Structure"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2472","DOI":"10.1093\/eurheartj\/ehm339","article-title":"Pacemaker current (If) in the human sinoatrial node","volume":"28","author":"Verkerk","year":"2007","journal-title":"Eur. Heart J."},{"key":"ref_38","first-page":"904","article-title":"Single cells isolated from human sinoatrial node: Action potentials and numerical reconstruction of pacemaker current","volume":"2007","author":"Verkerk","year":"2007","journal-title":"Conf. Proc. IEEE Eng. Med. Biol. Soc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.yjmcc.2009.09.020","article-title":"Relative importance of funny current in human versus rabbit sinoatrial node","volume":"48","author":"Verkerk","year":"2010","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"507872","DOI":"10.1155\/2013\/507872","article-title":"Calcium transient and sodium-calcium exchange current in human versus rabbit sinoatrial node pacemaker cells","volume":"2013","author":"Verkerk","year":"2013","journal-title":"Sci. World J."},{"key":"ref_41","first-page":"H301","article-title":"Ionic mechanisms underlying human atrial action potential properties: Insights from a mathematical model","volume":"275","author":"Courtemanche","year":"1998","journal-title":"Am. J. Physiol."},{"key":"ref_42","first-page":"S410","article-title":"HCN4 current during human sinoatrial node action potentials","volume":"7","author":"Hoekstra","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s11517-006-0127-0","article-title":"Computer modelling of the sinoatrial node","volume":"45","author":"Wilders","year":"2007","journal-title":"Med. Biol. Eng. Comput."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1161\/CIRCULATIONAHA.108.789677","article-title":"Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: A molecular basis for tachycardia-bradycardia syndrome","volume":"119","author":"Yeh","year":"2009","journal-title":"Circulation"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1111\/jce.12212","article-title":"Chronic atrial fibrillation alters the functional properties of If in the human atrium","volume":"24","author":"Stillitano","year":"2013","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.yjmcc.2010.12.017","article-title":"Molecular architecture of the human specialised atrioventricular conduction axis","volume":"50","author":"Greener","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1073\/pnas.1010122108","article-title":"Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4","volume":"108","author":"Baruscotti","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1161\/CIRCEP.111.963421","article-title":"Molecular analysis of patterning of conduction tissues in the developing human heart","volume":"4","author":"Sizarov","year":"2011","journal-title":"Circ. Arrhythm. Electrophysiol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1446","DOI":"10.1093\/eurheartj\/ehq508","article-title":"Left ventricular non-compaction revisited: A distinct phenotype with genetic heterogeneity?","volume":"32","author":"Oechslin","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1152\/physrev.00029.2008","article-title":"Hyperpolarization-activated cation channels: From genes to function","volume":"89","author":"Biel","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.yjmcc.2012.05.013","article-title":"A caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins","volume":"53","author":"Barbuti","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s00424-003-1127-7","article-title":"KCNE2 modulates current amplitudes and activation kinetics of HCN4: Influence of KCNE family members on HCN4 currents","volume":"446","author":"Decher","year":"2003","journal-title":"Pfl\u00fcg. Arch."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1085\/jgp.200609648","article-title":"Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2","volume":"128","author":"Pian","year":"2006","journal-title":"J. Gen. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.yjmcc.2006.09.018","article-title":"Localization of f-channels to caveolae mediates specific \u03b22-adrenergic receptor modulation of rate in sinoatrial myocytes","volume":"42","author":"Barbuti","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"12312","DOI":"10.1021\/bi8009295","article-title":"Caveolin-3 associates with and affects the function of hyperpolarization-activated cyclic nucleotide-gated channel 4","volume":"47","author":"Ye","year":"2008","journal-title":"Biochemistry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.yjmcc.2009.01.010","article-title":"In situ co-distribution and functional interactions of SAP97 with sinoatrial isoforms of HCN channels","volume":"46","author":"Peters","year":"2009","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1113\/jphysiol.2002.027698","article-title":"Heteromeric HCN1-HCN4 channels: A comparison with native pacemaker channels from the rabbit sinoatrial node","volume":"549","author":"Altomare","year":"2003","journal-title":"J. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/2\/3071\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T20:42:07Z","timestamp":1760215327000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/16\/2\/3071"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,29]]},"references-count":57,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2015,2]]}},"alternative-id":["ijms16023071"],"URL":"https:\/\/doi.org\/10.3390\/ijms16023071","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,1,29]]}}}