Abstract
The neurosecretory anterior pituitary GH(4)C(1) cells exhibit the high voltage-activated dihydropyridine-sensitive L-type and the low voltage-activated T-type calcium currents. The activity of L-type calcium channels is tightly coupled to secretion of prolactin and other hormones in these cells. Depolarization induced by elevated extracellular K(+) reduces the dihydropyridine (+)-[(3)H]PN200-110 binding site density and (45)Ca(2+) uptake in these cells (). This study presents a functional analysis by electrophysiological techniques of short term regulation of L-type Ca(2+) channels in GH(4)C(1) cells by membrane depolarization. Depolarization of GH(4)C(1) cells by 50 mm K(+) rapidly reduced the barium currents through L-type calcium channels by approximately 70% and shifted the voltage dependence of activation by 10 mV to more depolarized potentials. Down-regulation depended on the strength of the depolarizing stimuli and was reversible. The currents recovered to near control levels on repolarization. Down-regulation of the calcium channel currents was calcium-dependent but may not have been due to excessive accumulation of intracellular calcium. Membrane depolarization by voltage clamping and by veratridine also produced a down-regulation of calcium channel currents. The down-regulation of the currents had an autocrine component. This study reveals a calcium-dependent down-regulation of the L-type calcium channel currents by depolarization.
Highlights
Voltage-gated Ca2ϩ channels control the flux of Ca2ϩ across the plasma membrane in a wide range of tissues and play a crucial role in many physiologic functions that include excitation-contraction and excitation-secretion coupling
This study presents a functional analysis by electrophysiological techniques of short term regulation of L-type Ca2؉ channels in GH4C1 cells by membrane depolarization
This study reveals a calciumdependent down-regulation of the L-type calcium channel currents by depolarization
Summary
Voltage-gated Ca2ϩ channels control the flux of Ca2ϩ across the plasma membrane in a wide range of tissues and play a crucial role in many physiologic functions that include excitation-contraction and excitation-secretion coupling. Persistent depolarization causes a slowly developing long term reduction in sustained 1,4-dihydropyridine-sensitive calcium channel current [20] Membrane depolarization reduces both low and high voltage-activated Ca2ϩ currents in molluscan neurons [21]. In the neuroendocrine GH4C1 cells, short term depolarization (up to 2 h) with elevated Kϩ produces a decrease in L-type Ca2ϩ channel density measured by 1,4-dihydropyridine binding and a corresponding decrease in channel function as measured by 45Ca2ϩ uptake into these cells. This decrease in the binding site density is ac-companied with an increase in affinity for the ligand as anticipated from voltage-dependent binding [22]. This work was designed to extend our previous study by characterizing electrophysiologically the short term regulation of L-type Ca2ϩ channels in GH4C1 cells by membrane depolar-
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