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Inhibition of Voltage-Dependent Calcium Channels by Prostaglandin E₂ in Rat Melanotrophs¹

Department of Physiology, University of Occupational and Environmental Health, School of Medicine, Kitakyushu 807, Japan

Address all correspondence and requests for reprints to: Izumi Shibuya, Ph.D., Department of Physiology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807 Japan. E-mail: shibuya{at}med.uoeh-u.ac.jp

The effects of PGE₂ on voltage-dependent Ca²⁺ channel currents were studied in dissociated rat melanotrophs by the whole-cell configuration of the patch-clamp technique. In about 90% of melanotrophs examined, PGE₂ reversibly inhibited voltage-dependent Ba²⁺ currents elicited by voltage steps from a holding potential of -80 to 0 mV, with an ED₅₀ of 68 nM. The maximum inhibition of Ba²⁺ currents by 1 µM PGE₂ (35.3%) was comparable with that by the maximally effective concentration (100 nM) of dopamine. The EP₁/EP₃ PGE (EP) agonists, 17PT-PGE₂ and sulprostone, and the EP₂/EP₃ agonist, misoprostol, mimicked the inhibition by PGE₂, whereas the selective EP₂ agonist, butaprostol, had little effect. The inhibition by PGE₂ was partially, but significantly, reduced by the selective EP₁ antagonist, SC-51322. The magnitude of the PGE₂-induced inhibition of Ba²⁺ currents was greatly reduced by pretreatment with pertussis toxin, or by a depolarizing prepulse, to +80 mV, lasting for 50 msec. Although four distinct types (N-, P/Q-, L-, and R-types) of high-threshold Ba²⁺ currents were observed, PGE₂ (1 µM) caused significant inhibition of only P/Q- and L-type currents, which were 17.3 and 10.1%, respectively, of the total Ba²⁺ currents.

These results suggest that PGE₂ inhibits P/Q- and L-type Ca²⁺ channels of rat melanotrophs via EP₁ and EP₃ receptors, which are coupled to pertussis toxin-sensitive G proteins, and produces both voltage-sensitive and -insensitive inhibition of Ca²⁺ channels.

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