PMID- 11264239 OWN - NLM STAT- MEDLINE DCOM- 20010517 LR - 20191210 IS - 0007-1188 (Print) IS - 0007-1188 (Linking) VI - 132 IP - 7 DP - 2001 Apr TI - Heterogeneous increases of cytoplasmic calcium: distinct effects on down-regulation of cell surface sodium channels and sodium channel subunit mRNA levels. PG - 1455-66 AB - 1. Long-term (> or = 12 h) treatment of cultured bovine adrenal chromaffin cells with A23187 (a Ca(2+) ionophore) or thapsigargin (TG) [an inhibitor of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)] caused a time- and concentration-dependent reduction of cell surface [(3)H]-saxitoxin (STX) binding capacity, but did not change the K:(D:) value. In A23187- or TG-treated cells, veratridine-induced (22)Na(+) influx was reduced (with no change in veratridine EC(50) value) while it was enhanced by alpha-scorpion venom, beta-scorpion venom, or Ptychodiscus brevis toxin-3, like in nontreated cells. 2. The A23187- or TG-induced decrease of [(3)H]-STX binding was diminished by BAPTA-AM. EGTA also inhibited the decreasing effect of A23187. A23187 caused a rapid, monophasic and persistent increase in intracellular concentration of Ca(2+) ([Ca(2+)](i)) to a greater extent than that observed with TG. 2,5-Di-(t-butyl)-1,4-benzohydroquinone (DBHQ) (an inhibitor of SERCA) produced only a rapid monophasic increase in [Ca(2+)](i), without any effect on [(3)H]-STX binding. 3. Reduction in [(3)H]-STX binding capacity induced by A23187 or TG was attenuated by Go6976 (an inhibitor of conventional protein kinase C) or calpastatin peptide (an inhibitor of calpain). When the internalization rate of cell surface Na(+) channels was measured in the presence of brefeldin A (an inhibitor of vesicular exit from the trans-Golgi network), A23187 or TG accelerated the reduction of [(3)H]-STX binding capacity. 4. Six hours treatment with A23187 lowered Na(+) channel alpha- and beta(1)-subunit mRNA levels, whereas TG had no effect. 5. These results suggest that elevation of [Ca(2+)](i) caused by A23187, TG or DBHQ exerted differential effects on down-regulation of cell surface functional Na(+) channels and Na(+) channel subunit mRNA levels. FAU - Shiraishi, S AU - Shiraishi S AD - Department of Pharmacology, Miyazaki Medical College, Miyazaki 889-1692, Japan. FAU - Shibuya, I AU - Shibuya I FAU - Uezono, Y AU - Uezono Y FAU - Yokoo, H AU - Yokoo H FAU - Toyohira, Y AU - Toyohira Y FAU - Yamamoto, R AU - Yamamoto R FAU - Yanagita, T AU - Yanagita T FAU - Kobayashi, H AU - Kobayashi H FAU - Wada, A AU - Wada A LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Br J Pharmacol JT - British journal of pharmacology JID - 7502536 RN - 0 (Calcium-Binding Proteins) RN - 0 (Carbazoles) RN - 0 (Enzyme Inhibitors) RN - 0 (Hydroquinones) RN - 0 (Indoles) RN - 0 (Ionophores) RN - 0 (Marine Toxins) RN - 0 (Oxocins) RN - 0 (Protein Subunits) RN - 0 (RNA, Messenger) RN - 0 (Scorpion Venoms) RN - 0 (Sodium Channels) RN - 10028-17-8 (Tritium) RN - 136194-77-9 (Go 6976) RN - 139890-68-9 (1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester) RN - 20350-15-6 (Brefeldin A) RN - 26XK13B61B (2,5-di-tert-butylhydroquinone) RN - 35523-89-8 (Saxitoxin) RN - 37H9VM9WZL (Calcimycin) RN - 526U7A2651 (Egtazic Acid) RN - 67526-95-8 (Thapsigargin) RN - 71-62-5 (Veratridine) RN - 79079-11-1 (calpastatin) RN - 85079-48-7 (brevetoxin T17) RN - 9NEZ333N27 (Sodium) RN - EC 3.4.22.- (Calpain) RN - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases) RN - EC 7.2.2.10 (Calcium-Transporting ATPases) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Binding, Competitive/drug effects MH - Brefeldin A/pharmacology MH - Calcimycin/pharmacology MH - Calcium/*metabolism/pharmacology MH - Calcium-Binding Proteins/pharmacology MH - Calcium-Transporting ATPases/antagonists & inhibitors MH - Calpain/antagonists & inhibitors MH - Carbazoles/pharmacology MH - Cattle MH - Cells, Cultured MH - Chromaffin Cells/drug effects/metabolism MH - Dose-Response Relationship, Drug MH - Down-Regulation MH - Egtazic Acid/analogs & derivatives/pharmacology MH - Enzyme Inhibitors/pharmacology MH - Hydroquinones/pharmacology MH - Indoles/pharmacology MH - Ionophores/pharmacology MH - Marine Toxins/pharmacology MH - *Oxocins MH - Protein Subunits MH - RNA, Messenger/drug effects/genetics/metabolism MH - Sarcoplasmic Reticulum Calcium-Transporting ATPases MH - Saxitoxin/metabolism MH - Scorpion Venoms/pharmacology MH - Sodium/metabolism MH - Sodium Channels/drug effects/genetics/*metabolism MH - Thapsigargin/pharmacology MH - Time Factors MH - Tritium MH - Veratridine/pharmacology PMC - PMC1572695 EDAT- 2001/03/27 10:00 MHDA- 2001/05/18 10:01 PMCR- 2002/04/01 CRDT- 2001/03/27 10:00 PHST- 2001/03/27 10:00 [pubmed] PHST- 2001/05/18 10:01 [medline] PHST- 2001/03/27 10:00 [entrez] PHST- 2002/04/01 00:00 [pmc-release] AID - 0703960 [pii] AID - 10.1038/sj.bjp.0703960 [doi] PST - ppublish SO - Br J Pharmacol. 2001 Apr;132(7):1455-66. doi: 10.1038/sj.bjp.0703960.