Pharmacological blockade of ERG K+ channels and Ca2+ influx through store-operated channels exerts opposite effects on intracellular Ca2+ oscillations in pituitary GH(3) cells

Citation
A. Secondo et al., Pharmacological blockade of ERG K+ channels and Ca2+ influx through store-operated channels exerts opposite effects on intracellular Ca2+ oscillations in pituitary GH(3) cells, MOLEC PHARM, 58(5), 2000, pp. 1115-1128
Citations number
41
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
MOLECULAR PHARMACOLOGY
ISSN journal
0026-895X → ACNP
Volume
58
Issue
5
Year of publication
2000
Pages
1115 - 1128
Database
ISI
SICI code
0026-895X(200011)58:5<1115:PBOEKC>2.0.ZU;2-#
Abstract
In the present study, the effects on intracellular calcium concentration ([ Ca2+](i)) oscillations of the blockade of ether-a-gogo-related gene (ERG) K + channels and of Ca2+ influx through store-operated channels (SOC) activat ed by [Ca2+](i) store depletion have been studied in GH(3) cells by means o f a combination of single-cell fura-2 microfluorimetry and whole-cell mode of the patch-clamp technique. Nanomolar concentrations (1-30 nM) of the pip eridinic second-generation antihistamines terfenadine and astemizole and of the class III antiarrhythmic methanesulfonanilide dofetilide, by blocking ERG K+ channels, increased the frequency and the amplitude of [Ca2+](i) osc illations in resting oscillating GH(3) cells. These compounds also induced the appearance of an oscillatory pattern of [Ca2+](i) in a subpopulation of nonoscillating GH(3) cells. The effects of ERG K+ channel blockade on [Ca2 +](i) oscillations appeared to be due to the activation of L-type Ca2+ chan nels, because they were prevented by 300 nM nimodipine. By contrast, the pi perazinic second-generation antihistamine cetirizine (0.01-30 mu M), which served as a negative control, failed to affect ERG K+ channels and did not interfere with [Ca2+](i) oscillations in GH(3) cells. Interestingly, microm olar concentrations of terfenadine and astemizole (0.3-30 mu M), but not of dofetilide (10-100 mu M), produced an inhibition of the spontaneous oscill atory pattern of [Ca2+](i) changes. This effect was possibly related to an inhibition of SOC, because these compounds inhibited the increase of [Ca2+] (i) achieved by extracellular calcium reintroduction after intracellular ca lcium store depletion with the sarcoplasmic or endoplasmic reticulum calciu m ATPase pump inhibitor thapsigargin (10 mu M) in an extracellular calcium- free medium. The same inhibitory effect on [Ca2+](i) oscillations and SOC w as observed with the first-generation antihistamine hydroxyzine (1-30 mu M) , the more hydrophobic metabolic precursor of cetirizine. Collectively, the results of the present study obtained with compounds that interfere in a d ifferent concentration range with ERG K+ channels or SOC suggest that 1) ER G K+ channels play a relevant role in controlling the oscillatory pattern o f [Ca2+](i) in resting GH(3) cells and 2) the inhibition of SOC might induc e an opposite effect, i.e., an inhibition of [Ca2+](i) oscillations.