Аннотация
OBJECTIVE: Activity of single L-type calcium channels (LTCC) is
enhanced in human failing myocardium (Circulation 98 (1998) 969.),
most likely due to impaired dephosphorylation. Protein phosphatase
2B (calcineurin) has recently been shown to be involved in heart
failure pathophysiology. We now focus on the regulation of single
LTCC by calcineurin that were prevented by Ca$^2+$-free experimental
conditions in our previous study. METHODS: Single LTCC currents
were recorded in myocytes from human atrium and ventricle. Charge
carriers were 70 mM Ba$^2+$, or a mixture of 30 mM Ca$^2+$
and 60 mM Ba$^2+$ to facilitate Ca$^2+$ permeation through
recorded channels. The calcineurin inhibitor cyclosporine (10 microM)
was used to reveal a putative role for calcineurin in regulation
of LTCC. RESULTS: A mixture of Ca$^2+$ and Ba$^2+$ as charge
carriers allowed for Ca$^2+$ permeation through recombinant human
embryonic kidney cells and native (atrial and ventricular) human
cardiac LTCC. With only Ba$^2+$ as the charge carrier, activities
of both ventricular and atrial LTCC were strongly decreased by
cyclosporine. In contrast, channel activity remained constant when
Ca$^2+$ permeation was provided. In the presence of thapsigargin
and (S)-BayK 8644, cyclosporine here even increased channel activity.
CONCLUSIONS: We propose a dual cyclosporine effect on human cardiac
LTCC. A non-specific inhibitory effect prevails with Ba$^2+$
permeation but can be compensated or overcome by a specific Ca$^2+$-dependent
stimulation with Ca$^2+$ permeation. More complete restoration
of physiological Ca$^2+$ movements (e.g., Ca$^2+$ release
from sarcoplasmic reticulum) will help to define even more precisely
the involvement of calcineurin in regulation of human cardiac LTCC.
- 14871552
- atria,
- barium,
- calcineurin,
- calcium
- calcium,
- cell
- cells,
- channels,
- congestive,
- cyclosporine,
- failure,
- gov't,
- heart
- heart,
- humans,
- l-type,
- line,
- membrane
- muscle
- non-u.s.
- p.h.s.,
- potentials,
- proteins,
- recombinant
- research
- support,
- u.s.
- ventricles,
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