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Constitutive β 2 ‐adrenergic signalling enhances sarcoplasmic reticulum Ca 2+ cycling to augment contraction in mouse heart
Author(s) -
Zhou YingYing,
Song LongSheng,
Lakatta Edward G.,
Xiao RuiPing,
Cheng Heping
Publication year - 1999
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.1999.00351.x
Subject(s) - contraction (grammar) , myofilament , endoplasmic reticulum , biophysics , myocyte , chemistry , medicine , inverse agonist , agonist , gating , ryanodine receptor , endocrinology , receptor , biology , biochemistry
1 Transgenic overexpression of the β 2 ‐adrenergic receptor (β 2 AR) in mouse heart augments baseline cardiac function in a ligand‐independent manner, due to the presence of spontaneously active β 2 AR (β 2 AR*). This study aims to elucidate the mechanism of β 2 AR*‐mediated modulation of cardiac excitation‐contraction (EC) coupling. 2 Confocal imaging was used to analyse Ca 2+ sparks and spatially resolve Ca 2+ transients in single ventricular myocytes from transgenic (TG4) and non‐transgenic (NTG) littermates. Whole‐cell voltage‐ and current‐clamp techniques were used to record L‐type Ca 2+ currents ( I Ca ) and action potentials, respectively. 3 In the absence of any β 2 AR ligand, TG4 myocytes had greater contraction amplitudes, larger Ca 2+ transients and faster relaxation times than did NTG cells. 4 The action potentials of TG4 and NTG myocytes were similar, except for a prolonged end‐stage repolarization in TG4 cells; the I Ca density and kinetics were nearly identical. The relationship between peak Ca 2+ and contraction, which reflects myofilament Ca 2+ sensitivity, was similar. 5 In TG4 cells, the frequency of Ca 2+ sparks (spontaneous or evoked at ‐40 mV) was 2‐7 times greater, despite the absence of change in the resting Ca 2+ , sarcoplasmic reticulum (SR) Ca 2+ content, and I Ca . Individual sparks were brighter, broader and lasted longer, leading to a 2.3‐fold greater signal mass. Thus, changes in both spark frequency and size underlie the greater Ca 2+ transient in TG4 cells. 6 The inverse agonist ICI 118,551 (ICI, 5 × 10 − 7 M), which blocks spontaneous β 2 AR activation, reversed the aforementioned β 2 AR* effects on cardiac EC coupling without affecting the sarcolemmal I Ca . However, ICI failed to detect significant constitutive β 2 AR activity in NTG cells. 7 We conclude that β 2 AR*‐mediated signalling enhances SR release channel activity and Ca 2+ ‐induced Ca 2+ release in TG4 cardiac myocytes, and that β 2 AR* enhances EC coupling by reinforcing SR Ca 2+ cycling (release and reuptake), but bypassing the sarcolemmal I Ca .