Document Detail


Distinct localization and modulation of Cav1.2 and Cav1.3 L-type Ca2+ channels in mouse sinoatrial node.
MedLine Citation:
PMID:  23045342     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dysregulation of L-type Ca(2+) currents in sinoatrial nodal (SAN) cells causes cardiac arrhythmia. Both Ca(v)1.2 and Ca(v)1.3 channels mediate sinoatrial L-type currents. Whether these channels exhibit differences in modulation and localization, which could affect their contribution to pacemaking, is unknown. In this study, we characterized voltage-dependent facilitation (VDF) and subcellular localization of Ca(v)1.2 and Ca(v)1.3 channels in mouse SAN cells and determined how these properties of Ca(v)1.3 affect sinoatrial pacemaking in a mathematical model. Whole cell Ba(2+) currents were recorded from SAN cells from mice carrying a point mutation that renders Ca(v)1.2 channels relatively insensitive to dihydropyridine antagonists. The Ca(v)1.2-mediated current was isolated in the presence of nimodipine (1 μm), which was subtracted from the total current to yield the Ca(v)1.3 component. With strong depolarizations (+80 mV), Ca(v)1.2 underwent significantly stronger inactivation than Ca(v)1.3. VDF of Ca(v)1.3 was evident during recovery from inactivation at a time when Ca(v)1.2 remained inactivated. By immunofluorescence, Ca(v)1.3 colocalized with ryanodine receptors in sarcomeric structures while Ca(v)1.2 was largely restricted to the delimiting plasma membrane. Ca(v)1.3 VDF enhanced recovery of pacemaker activity after pauses and positively regulated pacemaking during slow heart rate in a numerical model of mouse SAN automaticity, including preferential coupling of Ca(v)1.3 to ryanodine receptor-mediated Ca(2+) release. We conclude that strong VDF and colocalization with ryanodine receptors in mouse SAN cells are unique properties that may underlie a specific role for Ca(v)1.3 in opposing abnormal slowing of heart rate.
Authors:
Carl J Christel; Natalia Cardona; Pietro Mesirca; Stefan Herrmann; Franz Hofmann; Joerg Striessnig; Andreas Ludwig; Matteo E Mangoni; Amy Lee
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-08
Journal Detail:
Title:  The Journal of physiology     Volume:  590     ISSN:  1469-7793     ISO Abbreviation:  J. Physiol. (Lond.)     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-06-13     Revised Date:  2013-12-18    
Medline Journal Info:
Nlm Unique ID:  0266262     Medline TA:  J Physiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  6327-42     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Biological Clocks* / drug effects
Calcium Channel Blockers / pharmacology
Calcium Channels, L-Type / deficiency,  drug effects,  genetics,  metabolism*
Calcium Signaling* / drug effects
Computer Simulation
Dihydropyridines / pharmacology
Female
Fluorescent Antibody Technique
Heart Rate* / drug effects
Male
Membrane Potentials
Mice
Mice, Knockout
Mice, Transgenic
Models, Cardiovascular
Patch-Clamp Techniques
Point Mutation
Ryanodine Receptor Calcium Release Channel / metabolism
Sarcomeres / metabolism
Sinoatrial Node / drug effects,  metabolism*
Time Factors
Grant Support
ID/Acronym/Agency:
DC009433/DC/NIDCD NIH HHS; HL087120/HL/NHLBI NIH HHS; T32007121//PHS HHS
Chemical
Reg. No./Substance:
0/Cacna1d protein, mouse; 0/Calcium Channel Blockers; 0/Calcium Channels, L-Type; 0/Cav1.2 protein, mouse; 0/Dihydropyridines; 0/Ryanodine Receptor Calcium Release Channel
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Contribution of non-endothelium-dependent substances to exercise hyperaemia: are they O(2) dependent...
Next Document:  Direct and GABA-mediated indirect effects of nicotinic ACh receptor agonists on striatal neurones.