TRANSGENIC MANIPULATION OF BETA-ARK1 MODIFIES BETA1-AR RESPONSIVENESS

Project: Research project

Project Details

Description

Agonist-induced phosphorylation of beta-adrenergic receptors (beta-AR's)
by the beta-adrenergic receptor kinase 1 (betaARK1) in cell suspensions
can result in a rapid disruption of the normal coupling between receptors
and the stimulatory guanine nucleotide-binding protein Gs. To determine
the direct functional significance of betaARK1 on myocardial performance,
we measured the contractile responses to acute beta1-AR stimulation in
left ventricular myocytes isolated from control and transgenic mice
overexpressing either betaARK1 (TGbetaK12) or a betaARK1 inhibitor
(TGMini27). Contractile response to five concentrations (.01 to .10 _M) of
the beta1-AR agonist norepinephrine (NE) plus prazosin (1 _M) was
measured after a 60 second rest, i.e. the rested state contraction (RSC),
and during steady state (SSC) stimulation at 0.5 Hz (23_). At baseline,
there were no significant differences in RSC or SSC between control,
TGbK12 or TGMini27 mice. On the other hand, both the dose-response and
kinetics for the NE-induced SSC/RSC response were significantly different
among experimental groups (p lesser than 0.001). Specifically, the maximal
contractile response induced by NE in myocytes isolated from the
TGbetaK12 group was only 70% of the response observed in control cells,
and 50% of the response measured in TGMini27 cells. The evolution of the
NE contractile response in TGMini27 cells was 37% and 67% faster vs
control and TGbK12 cells, respectively (p lesser than 0.03). Thus,
substantial functional betaARK1 modulation of beta1-AR signalling occurs
in cardiac myocytes, even during short term 1-AR stimulation. These
results are consistent with a role for agonist-induced phosphorylation and
desensitization of cardiac beta1-AR's by betaARK1 in single myocytes, and
highlight the potential role of betaARK1 as an important determinant of
the cardiac beta1-AR contractile response. The findings of this study
have particular clinical relevance as they provide further support for the
use of betaARK1 inhibition as a potential therapeutic approach to improve
cardiac function in those humans with chronic heart failure, where
betaARK1 levels are known to be elevated.
StatusNot started

Funding

  • National Institute on Aging

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