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Multiple regulation by external ATP of nifedipine-insensitive, high voltage-activated Ca²⁺ current in guinea-pig mesenteric terminal arteriole

Hiromitsu Morita, Thapaliya Sharada*, Tadashi Takewaki*, Yushi Ito and Ryuji Inoue

We investigated the receptor-mediated regulation of nifedipine-insensitive, high voltage-activated Ca²⁺ currents in guinea-pig terminal mesenteric arterioles (I_mVDCC) using the whole-cell clamp technique. Screening of various vasoactive substances revealed that ATP, histamine and substance P exert modulatory effects on I_mVDCC. The effects of ATP on I_mVDCC after complete P2X receptor desensitization exhibited a complex concentration dependence. With 5 mM Ba²⁺, ATP potentiated I_mVDCC at low concentrations (~1-100 µM), but inhibited it at higher concentrations (>100 µM). The potentiating effects of ATP were abolished by suramin (100 µM) and PPADS (10 µM) and by intracellular application of GDPS (500 µM), whereas a substantial part of I_mVDCC inhibition by milimolar concentrations of ATP remained unaffected; due probably to its divalent cation chelating actions. In divalent cation-free solution, I_mVDCC was enlarged and underwent biphasic effects by ATPS and ADP, while 2-methylthio ATP (2MeSATP) exerted only inhibition, and pyrimidines such as UTP and UDP were ineffective. ATP-induced I_mVDCC potentiation was selectively inhibited by anti-G_s antibodies or protein kinase A (PKA) inhibitory peptides and mimicked by dibutyryl cAMP. In contrast, ATP-induced inhibition was selectively inhibited by G_q/11 antibodies or protein kinase C (PKC) inhibitory peptides and mimicked by PDBu. Pretreatment with pertussis toxin was ineffective. The apparent efficacy for I_mVDCC potentiation with PKC inhibitors was: ATPS > ATP≥ADP and for inhibition with PKA inhibitors was: 2MeSATP > ATPS > ATP > ADP. Neither I_mVDCC potentiation nor inhibition showed voltage dependence. These results suggest that I_mVDCC is multi-phasically regulated by external ATP via P2Y₁₁-resembling receptor/G_s/PKA pathway, P2Y₁-like receptor/G_q/11/PKC pathway, and metal chelation.

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