Cardiac excitation-contraction coupling in the absence of Na(+) - Ca2+ exchange.
We investigate cardiac excitation-contraction coupling in the absence of sarcolemmal Na(+) - Ca(2+) exchange using NCX1 knock out mice. Knock out of NCX1 is embryonic lethal, and we measure Ca(2+) transients and contractions in heart tubes from embryos at day 9.5 post coitum. Immunoblot and electron microscopy both indicate that sarcoplasmic reticular membranes are diminished in the knock out (NCX(-/-)) heart tubes. Both Ni(2+) and nifedipine block excitation-contraction coupling in NCX-containing (NCX+) and NCX(-/-) heart tubes indicating an essential role for the L-type Ca(2+) current. Under basal conditions (1Hz stimulation), the NCX(-/-) heart tubes have normal Ca(2+) transients but are unable to maintain homeostasis when Ca(2+) fluxes are increased by various interventions (increased stimulation frequency, caffeine, isoproterenol). In each case, the NCX(-/-) heart tubes respond to the intervention in a more deleterious manner (increased diastolic Ca(2+), decreased Ca(2+) transient) than the NCX+ heart tubes. Expression of the sarcolemmal Ca(2+) pump was not upregulated. The sarcolemmal Ca(2+) pump, however, was able to compensate surprisingly well for the absence of Na(+) - Ca(2+) exchange under basal conditions.
Reuter
Hannes
H
Departments of Physiology and Medicine and the Cardiovascular Research Laboratory, MRL 3-645, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1760, USA.
Henderson
Scott A
SA
Han
Tieyan
T
Mottino
Giuliano A
GA
Frank
Joy S
JS
Ross
Robert S
RS
Goldhaber
Joshua I
JI
Philipson
Kenneth D
KD
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D005333:Fetus; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009924:Organ Culture Techniques; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D012964:Sodium / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D002110:Caffeine; D012964:Sodium; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium