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Beta-adrenergic receptor desensitization in the early stage of hereditary cardiomyopathy in hamsters
S St-Onge1, P Chidiac, L Brakier-Gingras
1Département de biochimie et Groupe de recherche sur le système nerveux autonome, Université de Montréal, QC, Canada.
Insights
Early cardiomyopathy in Syrian hamsters impairs beta-adrenergic receptor (beta AR) signaling. This functional uncoupling, not a change in receptor density, reduces adenylyl cyclase activity, but this desensitization is temporary.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Signal Transduction
Background:
- Hereditary cardiomyopathy in Syrian hamsters affects cardiac function.
- The beta-adrenergic receptor (beta AR)/adenylyl cyclase pathway is crucial for cardiac regulation.
Purpose of the Study:
- To investigate the beta AR/adenylyl cyclase signaling pathway in Syrian hamster hearts during cardiomyopathy progression.
- To determine if changes in beta AR density or function contribute to cardiac dysfunction.
Main Methods:
- Cardiac membranes from cardiomyopathic Syrian hamsters at different disease stages were analyzed.
- Isoproterenol, fluoride, and forskolin-stimulated adenylyl cyclase activity were measured.
- [125I]iodocyanopindolol binding assays assessed beta AR density and distribution.
Main Results:
- A 32% decrease in isoproterenol-stimulated adenylyl cyclase activity was observed in prenecrotic (30-day-old) hamsters.
- No changes in fluoride- or forskolin-stimulated activity indicated receptor-mediated signaling impairment.
- Agonist binding properties were altered, with decreased guanyl nucleotide sensitivity, suggesting functional uncoupling of beta AR.
Conclusions:
- Early cardiomyopathy involves functional uncoupling of beta AR from adenylyl cyclase, without altering receptor density.
- This desensitization is transient, as signaling recovers in later stages of the disease.
Abstract:
The beta-adrenergic receptor (beta AR)/adenylyl cyclase signalling pathway was examined in cardiac membranes from cardiomyopathic Syrian hamsters. Three stages were examined during the progression of this hereditary cardiomyopathy (30 days old, prenecrotic phase; 60 days old, necrotic phase; and 120 days old, compensatory phase). Isoproterenol-stimulated adenylyl cyclase activity was decreased by 32 +/- 16% in 30-day-old cardiomyopathic hamsters, compared with age-matched controls. This was not accompanied by any change in the fluoride- or forskolin-stimulated activities, suggesting that the decrease reflects a perturbation of the receptor-mediated stimulation. Neither the density nor the subcellular distribution of the beta AR, as assessed by [125I]iodocyanopindolol binding assays, was affected in these animals. However, the agonist binding properties of the beta AR were significantly affected. Indeed, the effect of guanyl nucleotides on isoproterenol binding was decreased in 30-day-old cardiomyopathic hamsters. Given that guanyl nucleotide sensitivity is correlated with the ability of the beta AR to productively interact with Gs protein, these results suggest that the decreased beta-adrenergic-stimulated adenylyl cyclase activity results from a functional uncoupling of the beta AR with no change in receptor density. The desensitization of the beta-adrenergic-stimulated adenylyl cyclase was transient, since no change in isoproterenol-stimulated adenylyl cyclase was detected in 60- and 120-day-old hamsters, compared with age-matched controls. Similarly, the receptor number and distribution were not affected at those ages.(ABSTRACT TRUNCATED AT 250 WORDS)