HCN4 explained

Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 is a protein that in humans is encoded by the HCN4 gene.^{[1] [2] [3] [4]}

There are four HCN channels. HCN4 is prominently expressed in the pace maker region of the mammalian heart.^[5] Some humans with bradycardia and Sick sinus syndrome have been shown to have mutations in their HCN4 gene.^{[6] [7] [8]} The role of HCN channels in autonomic control of heart rate is currently a matter of ongoing investigation.^{[9] [10] [11] [12]}

Interactions

HCN4 has been shown to interact with HCN2.^[13]

See also

• Cyclic nucleotide-gated ion channel
• Funny current

Further reading

• Qu J, Altomare C, Bucchi A, DiFrancesco D, Robinson RB . Functional comparison of HCN isoforms expressed in ventricular and HEK 293 cells . Pflügers Archiv . 444 . 5 . 597–601 . Aug 2002 . 12194012 . 10.1007/s00424-002-0860-7 . 508732 .
• Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D . Pacemaker channel dysfunction in a patient with sinus node disease . The Journal of Clinical Investigation . 111 . 10 . 1537–45 . May 2003 . 12750403 . 155041 . 10.1172/JCI16387 .
• Stieber J, Thomer A, Much B, Schneider A, Biel M, Hofmann F . Molecular basis for the different activation kinetics of the pacemaker channels HCN2 and HCN4 . The Journal of Biological Chemistry . 278 . 36 . 33672–80 . Sep 2003 . 12813043 . 10.1074/jbc.M305318200 . free .
• Decher N, Bundis F, Vajna R, Steinmeyer K . KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents . Pflügers Archiv . 446 . 6 . 633–40 . Sep 2003 . 12856183 . 10.1007/s00424-003-1127-7 . 21513896 .
• Much B, Wahl-Schott C, Zong X, Schneider A, Baumann L, Moosmang S, Ludwig A, Biel M . Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels . The Journal of Biological Chemistry . 278 . 44 . 43781–6 . Oct 2003 . 12928435 . 10.1074/jbc.M306958200 . free .
• Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, Higashiuesato Y, Hirano Y, Yasunami M, Takishita S, Yamashina A, Ohe T, Sunamori M, Hiraoka M, Kimura A . Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia . The Journal of Biological Chemistry . 279 . 26 . 27194–8 . Jun 2004 . 15123648 . 10.1074/jbc.M311953200 . free .
• Michels G, Er F, Khan I, Südkamp M, Herzig S, Hoppe UC . Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias . Circulation . 111 . 4 . 399–404 . Feb 2005 . 15687126 . 10.1161/01.CIR.0000153799.65783.3A . free .
• Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D . Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel . The New England Journal of Medicine . 354 . 2 . 151–7 . Jan 2006 . 16407510 . 10.1056/NEJMoa052475 . free .
• Elinder F, Männikkö R, Pandey S, Larsson HP . Mode shifts in the voltage gating of the mouse and human HCN2 and HCN4 channels . The Journal of Physiology . 575 . Pt 2 . 417–31 . Sep 2006 . 16777944 . 1819464 . 10.1113/jphysiol.2006.110437 .
• Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, Dascal N, Eldar M, Glikson M . Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia . Circulation . 116 . 5 . 463–70 . Jul 2007 . 17646576 . 10.1161/CIRCULATIONAHA.107.706887 . free .

External links

• GeneReviews/NIH/NCBI/UW entry on Brugada syndrome

Notes and References

1. Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M . Two pacemaker channels from human heart with profoundly different activation kinetics . The EMBO Journal . 18 . 9 . 2323–9 . May 1999 . 10228147 . 1171315 . 10.1093/emboj/18.9.2323 .
2. Seifert R, Scholten A, Gauss R, Mincheva A, Lichter P, Kaupp UB . Molecular characterization of a slowly gating human hyperpolarization-activated channel predominantly expressed in thalamus, heart, and testis . Proceedings of the National Academy of Sciences of the United States of America . 96 . 16 . 9391–6 . Aug 1999 . 10430953 . 17793 . 10.1073/pnas.96.16.9391 . 1999PNAS...96.9391S . free .
3. Hofmann F, Biel M, Kaupp UB . International Union of Pharmacology. LI. Nomenclature and structure-function relationships of cyclic nucleotide-regulated channels . Pharmacological Reviews . 57 . 4 . 455–62 . Dec 2005 . 16382102 . 10.1124/pr.57.4.8 . 45853869 .
4. Web site: Entrez Gene: HCN4 hyperpolarization activated cyclic nucleotide-gated potassium channel 4.
5. Baruscotti M, Bucchi A, Viscomi C, Mandelli G, Consalez G, Gnecchi-Rusconi T, Montano N, Casali KR, Micheloni S, Barbuti A, DiFrancesco D . Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4 . Proceedings of the National Academy of Sciences of the United States of America . 108 . 4 . 1705–10 . Jan 2011 . 21220308 . 3029742 . 10.1073/pnas.1010122108 . 2011PNAS..108.1705B . free .
6. Jou . Chuanchau J. . Arrington . Cammon B. . Barnett . Spencer M . Shen . Jiaxiang . Cho . Scott . Sheng . Xiaoming . McCullagh . Patrick C. . Bowles . Neil E. . Pribble . Chase M. . Saarel . Elizabeth V. . Pilcher . Thomas A. . Etheridge . Susan P. . Tristani-Firouzi . Martin . A Functional Assay for Sick Sinus Syndrome Genetic Variants . Cellular Physiology and Biochemistry . 2017 . 42 . 5 . 2021–2029 . 10.1159/000479897 . 28803248 . english . 1015-8987. free .
7. Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D . Pacemaker channel dysfunction in a patient with sinus node disease . The Journal of Clinical Investigation . 111 . 10 . 1537–45 . May 2003 . 12750403 . 155041 . 10.1172/JCI16387 .
8. Laish-Farkash A, Glikson M, Brass D, Marek-Yagel D, Pras E, Dascal N, Antzelevitch C, Nof E, Reznik H, Eldar M, Luria D . A novel mutation in the HCN4 gene causes symptomatic sinus bradycardia in Moroccan Jews . Journal of Cardiovascular Electrophysiology . 21 . 12 . 1365–72 . Dec 2010 . 20662977 . 3005590 . 10.1111/j.1540-8167.2010.01844.x .
9. Larsson HP . How is the heart rate regulated in the sinoatrial node? Another piece to the puzzle . The Journal of General Physiology . 136 . 3 . 237–41 . Sep 2010 . 20713549 . 2931147 . 10.1085/jgp.201010506 .
10. Schweizer PA, Duhme N, Thomas D, Becker R, Zehelein J, Draguhn A, Bruehl C, Katus HA, Koenen M . cAMP sensitivity of HCN pacemaker channels determines basal heart rate but is not critical for autonomic rate control . Circulation: Arrhythmia and Electrophysiology . 3 . 5 . 542–52 . Oct 2010 . 20693575 . 10.1161/CIRCEP.110.949768 . free . 11858/00-001M-0000-002C-5DAB-C . free .
11. Liao Z, Lockhead D, Larson ED, Proenza C . Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node . The Journal of General Physiology . 136 . 3 . 247–58 . Sep 2010 . 20713547 . 2931151 . 10.1085/jgp.201010488 .
12. Nof E, Antzelevitch C, Glikson M . The Contribution of HCN4 to normal sinus node function in humans and animal models . Pacing and Clinical Electrophysiology . 33 . 1 . 100–6 . Jan 2010 . 19796353 . 2865562 . 10.1111/j.1540-8159.2009.02563.x .
13. Much B, Wahl-Schott C, Zong X, Schneider A, Baumann L, Moosmang S, Ludwig A, Biel M . Role of subunit heteromerization and N-linked glycosylation in the formation of functional hyperpolarization-activated cyclic nucleotide-gated channels . The Journal of Biological Chemistry . 278 . 44 . 43781–6 . Oct 2003 . 12928435 . 10.1074/jbc.M306958200 . free .