Copyright © 2005, European Society of Cardiology
Caveolae modulate excitation–contraction coupling and β2-adrenergic signalling in adult rat ventricular myocytes
Research Institute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9NQ, UK
* Corresponding author. Tel.: +44 113 343 4309; fax: +44 113 343 4228. Email address: s.c.calaghan{at}leeds.ac.uk
Objective: Caveolae, flask shaped invaginations of the cell membrane, influence signalling cascades in many cell types. We have tested the hypothesis that caveolae modulate excitation–contraction coupling (ECC) and β-adrenergic stimulation in the adult cardiac myocyte.
Methods: Shortening, [Ca2+]i and L-type Ca2+ current (ICa,L) were recorded in rat ventricular myocytes. Caveolae were disrupted with methyl-β-cyclodextrin (MβC).
Results: Shortening and [Ca2+]i transient amplitude were reduced in myocytes treated with MβC. MβC did not alter the density or characteristics of ICa,L or the sarcoplasmic reticulum (SR) Ca2+ load, but significantly reduced fractional SR Ca2+ release. The inotropic response of myocytes to β1-adrenoceptor stimulation was insensitive to caveolae disruption. By contrast, the increase in shortening, [Ca2+]i transient and ICa,L seen following β2 stimulation was markedly enhanced (3–5 fold) following MβC treatment, and the effect on ICa,L could be mimicked by dialyzing cells with an antibody to caveolin 3. When the G
i pathway was disabled with pertussis toxin (PTX), control cells showed a similar response to β2 stimulation as seen in MβC-treated myocytes, whereas MβC-treated cells were insensitive to PTX.
Conclusions: Caveolae modulate ECC via the efficiency of the Ca2+-induced Ca2+ release process, rather than Ca2+ influx. Our data are also consistent with the hypothesis that interaction of Gi protein cascade components with caveolin in the caveolae is necessary for effective signalling by this pathway. This suggests that changes in caveolin expression in the adult heart seen during aging and in disease will have consequences for baseline cardiac function and β-adrenergic responsiveness.
KEYWORDS Caveolae; Calcium; Adrenergic agonists; Ca-channel; Signal transduction
Time for primary review 34 days
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