NDLI: Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Content Provider	Springer Nature Link
Author	Chan, Yau Chi Wang, Kai Wing Au, Ka Lau, Chu Pak Tse, Hung Fat Li, Ronald A.
Copyright Year	2009
Abstract	If (or Ih), encoded by the hyperpolarization-activated, cyclic nucleotide-gated (HCN1–4) channel gene family, contributes significantly to cardiac pacing. Bradycardic agents such as ZD7288 that target HCN channels have been developed, but the molecular configuration of their receptor is poorly defined. Here, we probed the drug receptor by systematically introducing alanine scanning substitutions into the selectivity filter (C347A, I348A, G349A, Y350A, G351A in the P-loop), outer (P355A, V356A, S357A, M358A in the P-S6 linker), and inner (M377A, F378A, V379A in S6) pore vestibules of HCN1 channels. When heterologously expressed in human embryonic kidney 293 cells for patch-clamp recordings, I348A, G349A, Y350A, G351A, P355A, and V356A did not produce measurable currents. The half-blocking concentration (IC50) of wild type (WT) for ZD7288 was 25.8 ± 9.7 μM. While the IC50 of M358A was identical to WT, those of C347A, S357A, F378A, and V379A markedly increased to 137.6 ± 56.4, 113.3 ± 34.1, 587.1 ± 167.5, and 1726.3 ± 673.4 μM, respectively (p < 0.05). Despite the proximity of the S6 residues studied, M377A was hypersensitive (IC50 = 5.1 ± 0.7 μM; p < 0.05) implicating site specificity. To explore the energetic interactions among the S6 residues, double and triple substitutions (M377A/F378A, M377A/V379A, F378A/V379A, and M377A/F378A/V379A) were generated for thermodynamic cycle analysis. Specific interactions with coupling energies (ΔΔG) >1 kT for M377–F378 and F378–V379 but not M377–V379 were identified. Based on these new data and others, we proposed a refined drug-blocking model that may lead to improved antiarrhythmics and bioartificial pacemaker designs.
Starting Page	25
Ending Page	38
Page Count	14
File Format	PDF
ISSN	00316768
Journal	Pflügers Archiv
Volume Number	459
Issue Number	1
e-ISSN	14322013
Language	English
Publisher	Springer-Verlag
Publisher Date	2009-09-08
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Drug Inner pore ZD7288 Pacemaker channels HCN Human Physiology
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Erratum to: Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Erratum to: Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Probing S4 and S5 segment proximity in mammalian hyperpolarization-activated HCN channels by disulfide bridging and Cd2+ coordination

Pathophysiology of HCN channels

HCN-related channelopathies

State-Dependent Accessibility of the P-S6 Linker of Pacemaker (HCN) Channels Supports a Dynamic Pore-to-Gate Coupling Model

Allosteric regulation of the P2X4 receptor channel pore dilation

Ion binding in the Open HCN Pacemaker Channel Pore: Fast Mechanisms to Shape “Slow” Channels

Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Similar Documents

Erratum to: Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Erratum to: Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels

Probing S4 and S5 segment proximity in mammalian hyperpolarization-activated HCN channels by disulfide bridging and Cd2+ coordination

Pathophysiology of HCN channels

HCN-related channelopathies

State-Dependent Accessibility of the P-S6 Linker of Pacemaker (HCN) Channels Supports a Dynamic Pore-to-Gate Coupling Model

Allosteric regulation of the P2X4 receptor channel pore dilation

Ion binding in the Open HCN Pacemaker Channel Pore: Fast Mechanisms to Shape “Slow” Channels

Probing the bradycardic drug binding receptor of HCN-encoded pacemaker channels