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1 Department of Pharmacology and Physiology, The University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA2 Department of Physiology, Tokyo Medical University, Tokyo, Japan
The effects of changing cytosolic [Mg2+] ([Mg2+]i) on L-type Ca2+ currents were investigated in rat cardiac ventricular myocytes voltage-clamped with patch pipettes containing salt solutions with defined [Mg2+] and [Ca2+]. To control [Mg2+]i and cytosolic [Ca2+] ([Ca2+]i), the pipette solution included 30 mM citrate and 10 mM ATP along with 5 mM EGTA (slow Ca2+ buffer) or 15 mM EGTA plus 5 mM BAPTA (fast Ca2+ buffer). With pipette [Ca2+] ([Ca2+]p) set at 100 nM using a slow Ca2+ buffer and pipette [Mg2+] ([Mg2+]p) set at 0.2 mM, peak L-type Ca2+ current density (ICa) was 17.0 ± 2.2 pA pF-1. Under the same conditions, but with [Mg2+]p set to 1.8 mM, ICa was 5.6 ± 1.0 pA pF-1, a 64 ± 2.8% decrease in amplitude. This decrease in ICa was accompanied by an acceleration and a –8 mV shift in the voltage dependence of current inactivation. The [Mg2+]p-dependent decrease in ICa was not significantly different when myocytes were preincubated with 10 µM forskolin and 300 µM 3-isobutyl-1-methylxanthine and voltage-clamped with pipettes containing 50 µM okadaic acid, to maximize Ca2+ channel phosphorylation. However, when myocytes were voltage-clamped with pipettes containing protein phosphatase 2A, to promote channel dephosphorylation, ICa decreased only 25 ± 3.4% on changing [Mg2+]p from 0.2 to 1.8 mM. In the presence of 0.2 mM[Mg2+]p, changing channel phosphorylation conditions altered ICa over a 4-fold range; however, with 1.8 mM[Mg2+]p, these same manoeuvres had a much smaller effect on ICa. These data suggest that [Mg2+]i can antagonize the effects of phosphorylation on channel gating kinetics. Setting [Ca2+]p to 1, 100 or 300 nM also showed that the [Mg2+]p-induced reduction of ICa was smaller at the lowest [Ca2+]p, irrespective of channel phosphorylation conditions. This interaction between [Ca2+]i and [Mg2+]i to modulate ICa was not significantly affected by ryanodine, fast Ca2+ buffers or inhibitors of calmodulin, calmodulin-dependent kinase and calcineurin. Thus, physiologically relevant [Mg2+]i modulates ICa by counteracting the effects of Ca2+ channel phosphorylation and by an unknown [Ca2+]i-dependent mechanism. The magnitude of these effects suggests that changes in [Mg2+]i could be critical in regulating L-type channel gating.
(Received 4 June 2003;
accepted after revision 12 November 2003;
first published online 14 November 2003)
Corresponding author J. R. Berlin: Department of Pharmacology and Physiology, The University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA. Email: berlinjr{at}umdnj.edu
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