TY - JOUR
T1 - Enhancement of rabbit cardiac sodium channels by β-adrenergic stimulation
AU - Matsuda, J. J.
AU - Lee, H.
AU - Shibata, E. F.
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 1992
Y1 - 1992
N2 - Voltage-dependent sodium channels from a variety of tissues are known to be phosphorylated by the cAMP-dependent protein kinase, protein kinase A. However, the functional significance of sodium channel phosphorylation is not clearly understood. Using whole-cell voltage-clamp techniques, we show that sodium currents (I(Na)s) in rabbit cardiac myocytes are enhanced by isoproterenol (ISO). This enhancement of I(Na) by ISO 1) is holding potential dependent, 2) can be mimicked by forskolin and dibutyryl cAMP, and 3) is accompanied by an increase in the rate of Na+ channel inactivation. In single-channel, inside-out patch experiments, the catalytic subunit of protein kinase A also enhances I(Na) and increases the rate of inactivation, suggesting that cardiac Na+ channel phosphorylation may be physiologically important. Addition of the protein kinase A inhibitor to the pipette solution in whole-cell experiments blocks the stimulatory effect of forskolin without blocking the effect of ISO, suggesting that ISO also enhances I(Na) through a cAMP-independent pathway. To determine if ISO may stimulate I(Na) through a direct G protein pathway, single channels were recorded in the presence of the G(s)-activating GTP analogue, GTPγS, and the stimulatory G protein subunit, G(sα). Both of these agents enhanced I(Na) without affecting the rate of Na+ channel inactivation. These results suggest that ISO enhances rabbit cardiac I(Na) through a dual (direct and indirect) G protein regulatory pathway.
AB - Voltage-dependent sodium channels from a variety of tissues are known to be phosphorylated by the cAMP-dependent protein kinase, protein kinase A. However, the functional significance of sodium channel phosphorylation is not clearly understood. Using whole-cell voltage-clamp techniques, we show that sodium currents (I(Na)s) in rabbit cardiac myocytes are enhanced by isoproterenol (ISO). This enhancement of I(Na) by ISO 1) is holding potential dependent, 2) can be mimicked by forskolin and dibutyryl cAMP, and 3) is accompanied by an increase in the rate of Na+ channel inactivation. In single-channel, inside-out patch experiments, the catalytic subunit of protein kinase A also enhances I(Na) and increases the rate of inactivation, suggesting that cardiac Na+ channel phosphorylation may be physiologically important. Addition of the protein kinase A inhibitor to the pipette solution in whole-cell experiments blocks the stimulatory effect of forskolin without blocking the effect of ISO, suggesting that ISO also enhances I(Na) through a cAMP-independent pathway. To determine if ISO may stimulate I(Na) through a direct G protein pathway, single channels were recorded in the presence of the G(s)-activating GTP analogue, GTPγS, and the stimulatory G protein subunit, G(sα). Both of these agents enhanced I(Na) without affecting the rate of Na+ channel inactivation. These results suggest that ISO enhances rabbit cardiac I(Na) through a dual (direct and indirect) G protein regulatory pathway.
KW - isoproterenol
KW - protein kinase A
KW - sodium channels
KW - β-adrenergic stimulation
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U2 - 10.1161/01.res.70.1.199
DO - 10.1161/01.res.70.1.199
M3 - Article
C2 - 1309315
AN - SCOPUS:0026505405
VL - 70
SP - 199
EP - 207
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 1
ER -