The mechanism of actions of 3-(5'-(hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) on Ca(2+)-activated K(+) currents in GH(3) lactotrophs.
The effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), an activator of soluble guanylyl cyclase, on ionic currents have been assessed in rat pituitary GH(3) lactotrophs. In GH(3) cells bathed in normal Tyrode's solution, YC-1 (1 microM) reversibly suppressed the amplitude of the Ca(2+)-activated K(+) current (I(K(Ca))). YC-1 at a concentration above 10 microM produced a biphasic response in the amplitude of I(K(Ca)), i.e., an initial decrease followed by a sustained increase. When the pipette solutions were filled with high EGTA (10 mM), the YC-1-induced stimulatory effect on I(K(Ca)) was abolished. Over a similar concentration range, YC-1 also effectively inhibited the voltage-dependent K(+) current (I(K(V))) in GH(3) cells. The IC(50) value required for the inhibition of I(K(V)) by YC-1 was 1 microM. Unlike YC-1, 8-bromo cGMP did not inhibit I(K(Ca)). However, YC-1 (10 microM) did not affect the amplitude of L-type Ca(2+) current. In the cell-attached configuration, application of YC-1 (10 microM) to the bath did not change the single-channel conductance of the large-conductance Ca(2+)-activated K(+) (BK(Ca)) channels; however, it did increase the opening probability of BK(Ca) channels. In contrast, in the outside-out configuration, YC-1 (10 microM) significantly suppressed the opening probability of BK(Ca) channels. The present study shows dual effects of YC-1 on I(K(Ca)) in GH(3) cells. The YC-1-mediated stimulation of I(K(Ca)) may result from elevated cytosolic Ca(2+), whereas the inhibition of I(K(Ca)) and I(K(V)) by YC-1 appears to be direct and independent of the activation of soluble guanylyl cyclase. Caution thus needs to be used in attributing the YC-1-mediated response to the activation of soluble guanylyl cyclase.
Wu
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Department of Medical Research and Education, Veterans General Hospital-Kaohsiung, 386, Ta-Chung 1st Road, Kaohsiung, Taiwan, ROC. snwu@isca.vghks.gov.tw
Hwang
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Teng
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Li
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Jan
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D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D007191:Indazoles / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014407:Tumor Cells, Cultured
D020746:Calcium Channels, L-Type; D007191:Indazoles; D015221:Potassium Channels; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D002118:Calcium