International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

F50 Bradyarrhythmias and Congestive Heart Failure in the Mice Defective in the M1 Muscarinic Receptor/PLC-1 Signaling

Woo, S-H.1, Hwang, J-Y.1, Kim, S-S.1,3, Lee, B-H.4, Namkung, Y.1,2, Lee, C-O.1, Kim, D.1,2, and Shin, H-S.1,2. 1Department of Life Science, and 2National CRI Center for Calcium & Learning, POSTECH, Pohang, 790-784, Korea; 3Department of Pathology, Ulsan University Hospital, Ulsan, Korea; 4Korea Research Institute of Chemical Technology, Taechon, Korea

Heart rate is regulated by two mutually antagonizing systems: the sympathetic system accelerating the rate via the beta-adrenergic receptor and the parasympathetic system slowing down the rate via the M2 muscarinic acetylcholine receptor (mAChR). Through the analysis of phospholipase C (PLC) b1 knockout mice, however, we demonstrate that the muscarinic system also has a stimulatory role via another mAChR isotype, M1, in the regulation of heart rate, and a defect in this role results in severe heart problems in vivo.

We first observed that PLC b1 was selectively coupled to muscarinic receptors in the heart in experiments measuring agonist-induced PLC activities. Then the cardiac responses to muscarinic stimulations were monitored in vitro by electrically recording autonomously beating atrial tissues. The response of the wild type atrium to a muscarinic agonist, carbachol, consisted of two phases: an immediate arrest followed by spontaneous recovery of beating. In contrast, the recovery phase was absent in the mutant atrium, indicating that PLC b1 was necessary for the recovery. Analysis using antagonists for different isotypes of mAChR showed that the arrest phase of the response was mediated by M2 and the recovery phase was dependent on M1. We conclude that the parasympathetic acetylcholine system plays dual opposing roles, inhibition vs stimulation, in the regulation of heart rate through two distinct receptor isotypes, and the stimulatory, M1, signaling is coupled to PLC b1.

The physiological consequence in vivo of the defect in the M1/PLC b1 signaling was examined by monitoring the electrocardiogram of the mutant mice. The mutant mice were normal until 1 month of age and thereafter began to develop bradyarrhythmias that eventually resulted in congestive heart failures as the mice get old. Interestingly, the expression of the M1 proteins in the heart followed the same developmental pattern as that of the expression of the cardiac phenotype of the PLC b1 mutation, i.e. M1 was not expressed in young hearts both of wild types and of mutants. These suggest that in young hearts the M1/PLC b1 signaling is not operating, and strengthen the idea that the PLC b1 is the mediator of the stimulatory effect of the M1 receptor.


Abstracts * Officers * Bylaws * Application Form * Meeting Calendar * Contact Information * Home * Resources * News and Views * Membership

Base url
Last modified: Saturday, November 3, 2012