The Journal of General Physiology
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

Published 1 February 2001. doi:10.1085/jgp.117.2.91
This Article
Right arrow Full Text
Right arrow Full Text (PDF, 267K)
Right arrow PPT slides of all figures
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JGP
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Shin, K. S.
Right arrow Articles by Yellen, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Shin, K. S.
Right arrow Articles by Yellen, G.
Social Bookmarking
 Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?
© The Rockefeller University Press, 0022-1295/2001//91/ $5.00
Journal of General Physiology, Volume 117, Number 2, 2001


Original Article

Blocker State Dependence and Trapping in Hyperpolarization-Activated Cation Channels

Evidence for an Intracellular Activation Gate



Ki Soon Shina, Brad S. Rothberga, and Gary Yellena

a Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115

Hyperpolarization-activated cation currents (Ih) are key determinants of repetitive electrical activity in heart and nerve cells. The bradycardic agent ZD7288 is a selective blocker of these currents. We studied the mechanism for ZD7288 blockade of cloned Ih channels in excised inside-out patches. ZD7288 blockade of the mammalian mHCN1 channel appeared to require opening of the channel, but strong hyperpolarization disfavored blockade. The steepness of this voltage-dependent effect (an apparent valence of ~4) makes it unlikely to arise solely from a direct effect of voltage on blocker binding. Instead, it probably indicates a differential affinity of the blocker for different channel conformations. Similar properties were seen for ZD7288 blockade of the sea urchin homologue of Ih channels (SPIH), but some of the blockade was irreversible. To explore the molecular basis for the difference in reversibility, we constructed chimeric channels from mHCN1 and SPIH and localized the structural determinant for the reversibility to three residues in the S6 region likely to line the pore. Using a triple point mutant in S6, we also revealed the trapping of ZD7288 by the closing of the channel. Overall, the observations led us to hypothesize that the residues responsible for ZD7288 block of Ih channels are located in the pore lining, and are guarded by an intracellular activation gate of the channel.

Key Words: mHCN1 • SPIH • ZD7288 • pore


© 2001 The Rockefeller University Press


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
Physiol. Rev.Home page
M. Biel, C. Wahl-Schott, S. Michalakis, and X. Zong
Hyperpolarization-Activated Cation Channels: From Genes to Function
Physiol Rev, July 1, 2009; 89(3): 847 - 885.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
V. Macri, H. Nazzari, E. McDonald, and E. A. Accili
Alanine Scanning of the S6 Segment Reveals a Unique and cAMP-sensitive Association between the Pore and Voltage-dependent Opening in HCN Channels
J. Biol. Chem., June 5, 2009; 284(23): 15659 - 15667.
[Abstract] [Full Text] [PDF]


Home page
Mol. Pharmacol.Home page
L. Cheng and M. C. Sanguinetti
Niflumic Acid Alters Gating of HCN2 Pacemaker Channels by Interaction with the Outer Region of S4 Voltage Sensing Domains
Mol. Pharmacol., May 1, 2009; 75(5): 1210 - 1221.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
N. A. Ramakrishnan, M. J. Drescher, R. L. Barretto, K. W. Beisel, J. S. Hatfield, and D. G. Drescher
Calcium-dependent Binding of HCN1 Channel Protein to Hair Cell Stereociliary Tip Link Protein Protocadherin 15 CD3
J. Biol. Chem., January 30, 2009; 284(5): 3227 - 3238.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
A. Jara-Oseguera, I. Llorente, T. Rosenbaum, and L. D. Islas
Properties of the Inner Pore Region of TRPV1 Channels Revealed by Block with Quaternary Ammoniums
J. Gen. Physiol., November 1, 2008; 132(5): 547 - 562.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
G. Kanaporis, G. Mese, L. Valiuniene, T. W. White, P. R. Brink, and V. Valiunas
Gap Junction Channels Exhibit Connexin-specific Permeability to Cyclic Nucleotides
J. Gen. Physiol., March 31, 2008; 131(4): 293 - 305.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
M. Vandecasteele, J. Glowinski, J.-M. Deniau, and L. Venance
Chemical transmission between dopaminergic neuron pairs
PNAS, March 25, 2008; 105(12): 4904 - 4909.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
A. K. Lyashchenko and G. R. Tibbs
Ion binding in the Open HCN Pacemaker Channel Pore: Fast Mechanisms to Shape "Slow" Channels
J. Gen. Physiol., February 25, 2008; 131(3): 227 - 243.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
A. Bruening-Wright, W.-S. Lee, J. P. Adelman, and J. Maylie
Evidence for a Deep Pore Activation Gate in Small Conductance Ca2+-activated K+ Channels
J. Gen. Physiol., November 26, 2007; 130(6): 601 - 610.
[Abstract] [Full Text] [PDF]


Home page
J. Pharmacol. Exp. Ther.Home page
L. Cheng, K. Kinard, R. Rajamani, and M. C. Sanguinetti
Molecular Mapping of the Binding Site for a Blocker of Hyperpolarization-Activated, Cyclic Nucleotide-Modulated Pacemaker Channels
J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 931 - 939.
[Abstract] [Full Text] [PDF]


Home page
J. Neurophysiol.Home page
X.-J. Cao, S. Shatadal, and D. Oertel
Voltage-Sensitive Conductances of Bushy Cells of the Mammalian Ventral Cochlear Nucleus
J Neurophysiol, June 1, 2007; 97(6): 3961 - 3975.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
T. M. Ishii, N. Nakashima, and H. Ohmori
Tryptophan-scanning mutagenesis in the S1 domain of mammalian HCN channel reveals residues critical for voltage-gated activation
J. Physiol., March 1, 2007; 579(2): 291 - 301.
[Abstract] [Full Text] [PDF]


Home page
Cardiovasc ResHome page
J. Liu, H. Dobrzynski, J. Yanni, M. R. Boyett, and M. Lei
Organisation of the mouse sinoatrial node: structure and expression of HCN channels
Cardiovasc Res, March 1, 2007; 73(4): 729 - 738.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
J. P. Dekker and G. Yellen
Cooperative Gating between Single HCN Pacemaker Channels
J. Gen. Physiol., November 1, 2006; 128(5): 561 - 567.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
D. L. Prole and G. Yellen
Reversal of HCN Channel Voltage Dependence via Bridging of the S4-S5 Linker and Post-S6
J. Gen. Physiol., August 28, 2006; 128(3): 273 - 282.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
C. M. Wilkens and R. W. Aldrich
State-independent Block of BK Channels by an Intracellular Quaternary Ammonium
J. Gen. Physiol., August 28, 2006; 128(3): 347 - 364.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
C. Proenza and G. Yellen
Distinct Populations of HCN Pacemaker Channels Produce Voltage-dependent and Voltage-independent Currents
J. Gen. Physiol., January 30, 2006; 127(2): 183 - 190.
[Abstract] [Full Text] [PDF]


Home page
J. Neurophysiol.Home page
A. R. A. Rodrigues and D. Oertel
Hyperpolarization-Activated Currents Regulate Excitability in Stellate Cells of the Mammalian Ventral Cochlear Nucleus
J Neurophysiol, January 1, 2006; 95(1): 76 - 87.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
D. del Camino, M. Kanevsky, and G. Yellen
Status of the Intracellular Gate in the Activated-not-open State of Shaker K+ Channels
J. Gen. Physiol., October 31, 2005; 126(5): 419 - 428.
[Abstract] [Full Text] [PDF]


Home page
J. Physiol.Home page
T. A Simeone, J. M Rho, and T. Z Baram
Single channel properties of hyperpolarization-activated cation currents in acutely dissociated rat hippocampal neurones
J. Physiol., October 15, 2005; 568(2): 371 - 380.
[Abstract] [Full Text] [PDF]


Home page
J. Biol. Chem.Home page
J. Stieber, G. Stockl, S. Herrmann, B. Hassfurth, and F. Hofmann
Functional Expression of the Human HCN3 Channel
J. Biol. Chem., October 14, 2005; 280(41): 34635 - 34643.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
C. Xie, X.-g. Zhen, and J. Yang
Localization of the Activation Gate of a Voltage-gated Ca2+ Channel
J. Gen. Physiol., August 29, 2005; 126(3): 205 - 212.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
A. L. Zimmerman
Capturing Ion Channel Gating: A Little Salt on the Tail Does the Trick
J. Gen. Physiol., November 29, 2004; 124(6): 627 - 629.
[Full Text] [PDF]


Home page
J. Neurosci.Home page
T. N. Doan, K. Stephans, A. N. Ramirez, P. A. Glazebrook, M. C. Andresen, and D. L. Kunze
Differential Distribution and Function of Hyperpolarization-Activated Channels in Sensory Neurons and Mechanosensitive Fibers
J. Neurosci., March 31, 2004; 24(13): 3335 - 3343.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
A. Dahlmann, M. Li, Z. Gao, D. McGarrigle, H. Sackin, and L. G. Palmer
Regulation of Kir Channels by Intracellular pH and Extracellular K+: Mechanisms of Coupling
J. Gen. Physiol., March 29, 2004; 123(4): 441 - 454.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
R. Horn
How S4 Segments Move Charge. Let Me Count the Ways
J. Gen. Physiol., December 29, 2003; 123(1): 1 - 4.
[Full Text] [PDF]


Home page
JGPHome page
S. Vemana, S. Pandey, and H. P. Larsson
S4 Movement in a Mammalian HCN Channel
J. Gen. Physiol., December 29, 2003; 123(1): 21 - 32.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
B. S. Rothberg, K. S. Shin, and G. Yellen
Movements near the Gate of a Hyperpolarization-activated Cation Channel
J. Gen. Physiol., October 27, 2003; 122(5): 501 - 510.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
D. Enkvetchakul and C.G. Nichols
Gating Mechanism of KATP Channels: Function Fits Form
J. Gen. Physiol., October 27, 2003; 122(5): 471 - 480.
[Full Text] [PDF]


Home page
Eur Heart J SupplHome page
D. DiFrancesco
If inhibition: a novel mechanism of action
Eur. Heart J. Suppl., September 1, 2003; 5(suppl_G): G19 - G25.
[Abstract] [PDF]


Home page
J CARDIOVASC PHARMACOL THERHome page
S. Yusuf and A. J. Camm
Sinus Tachyarrhythmias and the Specific Bradycardic Agents: A Marriage Made in Heaven?
Journal of Cardiovascular Pharmacology and Therapeutics, June 1, 2003; 8(2): 89 - 105.
[Abstract] [PDF]


Home page
J. Physiol.Home page
E. Rodriguez and A. Darszon
Intracellular sodium changes during the speract response and the acrosome reaction in sea urchin sperm
J. Physiol., January 1, 2003; 546(1): 89 - 100.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
H. P. Larsson
The Search Is on for the Voltage Sensor-to-gate Coupling
J. Gen. Physiol., September 30, 2002; 120(4): 475 - 481.
[Full Text] [PDF]


Home page
JGPHome page
A. Bucchi, M. Baruscotti, and D. DiFrancesco
Current-dependent Block of Rabbit Sino-Atrial Node If Channels by Ivabradine
J. Gen. Physiol., June 10, 2002; 120(1): 1 - 13.
[Abstract] [Full Text] [PDF]


Home page
Circ. Res.Home page
D. DiFrancesco and R. B. Robinson
{beta}-Modulation of Pacemaker Rate: Novel Mechanism or Novel Mechanics of an Old One?
Circ. Res., April 5, 2002; 90 (6): e69 - e69.
[Full Text] [PDF]


Home page
JGPHome page
B. S. Rothberg, K. S. Shin, P. S. Phale, and G. Yellen
Voltage-Controlled Gating at the Intracellular Entrance to a Hyperpolarization-Activated Cation Channel
J. Gen. Physiol., January 1, 2002; 119(1): 83 - 91.
[Abstract] [Full Text] [PDF]


Home page
JGPHome page
J. Wang, S. Chen, and S. A. Siegelbaum
Regulation of Hyperpolarization-Activated Hcn Channel Gating and Camp Modulation Due to Interactions of Cooh Terminus and Core Transmembrane Regions
J. Gen. Physiol., September 1, 2001; 118(3): 237 - 250.
[Abstract] [Full Text] [PDF]


Home page
Proc. Natl. Acad. Sci. USAHome page
J. Chen, J. S. Mitcheson, M. Tristani-Firouzi, M. Lin, and M. C. Sanguinetti
The S4-S5 linker couples voltage sensing and activation of pacemaker channels
PNAS, September 25, 2001; 98(20): 11277 - 11282.
[Abstract] [Full Text] [PDF]



  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents