PMID- 12411413
OWN - NLM
STAT- MEDLINE
DCOM- 20030408
LR  - 20181113
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 137
IP  - 6
DP  - 2002 Nov
TI  - Nitric oxide inhibits capacitative Ca2+ entry by suppression of mitochondrial 
      Ca2+ handling.
PG  - 821-30
AB  - 1. Nitric oxide (NO) is a key modulator of cellular Ca(2+) signalling and a 
      determinant of mitochondrial function. Here, we demonstrate that NO governs 
      capacitative Ca(2+) entry (CCE) into HEK293 cells by impairment of mitochondrial 
      Ca(2+) handling. 2. Authentic NO as well as the NO donors 
      1-[2-(carboxylato)pyrrolidin-1-yl]diazem-1-ium-1,2-diolate (ProliNO) and 
      2-(N,N-diethylamino)-diazenolate-2-oxide (DEANO) suppressed CCE activated by 
      thapsigargin (TG)-induced store depletion. Threshold concentrations for 
      inhibition of CCE by ProliNO and DEANO were 0.3 and 1 micro M, respectively. 3. 
      NO-induced inhibition of CCE was not mimicked by peroxynitrite (100 micro M), the 
      peroxynitrite donor 3-morpholino-sydnonimine (SIN-1, 100 micro M) or 
      8-bromoguanosine 3',5'-cyclic monophosphate (8-BrcGMP, 1 mM). In addition, the 
      guanylyl cyclase inhibitor 1H-[1,2,4] oxadiazole[4,3-a] quinoxalin-1-one (ODQ, 30 
      micro M) failed to antagonize the inhibitory action of NO on CCE. 4. DEANO (1-10 
      micro M) suppressed mitochondrial respiration as evident from inhibition of 
      cellular oxygen consumption. Experiments using fluorescent dyes to monitor 
      mitochondrial membrane potential and mitochondrial Ca(2+) levels, respectively, 
      indicated that DEANO (10 micro M) depolarized mitochondria and suppressed 
      mitochondrial Ca(2+) sequestration. The inhibitory effect of DEANO on Ca(2+) 
      uptake into mitochondria was confirmed by recording mitochondrial Ca(2+) during 
      agonist stimulation in HEK293 cells expressing ratiometric-pericam in 
      mitochondria. 5. DEANO (10 micro M) failed to inhibit Ba(2+) entry into 
      TG-stimulated cells when extracellular Ca(2+) was buffered below 1 micro M, while 
      clear inhibition of Ba(2+) entry into store depleted cells was observed when 
      extracellular Ca(2+) levels were above 10 micro M. Moreover, buffering of 
      intracellular Ca(2+) by use of N,N'-[1,2-ethanediylbis(oxy-2,1-phenylene)] bis 
      [N-[25-[(acetyloxy) methoxy]-2-oxoethyl]]-, bis[(acetyloxy)methyl] ester 
      (BAPTA/AM) eliminated inhibition of CCE by NO, indicating that the observed 
      inhibitory effects are based on an intracellular, Ca(2+) dependent-regulatory 
      process. 6. Our data demonstrate that NO effectively inhibits CCE cells by 
      cGMP-independent suppression of mitochondrial function. We suggest disruption of 
      local Ca(2+) handling by mitochondria as a key mechanism of NO induced 
      suppression of CCE.
FAU - Thyagarajan, Baskaran
AU  - Thyagarajan B
AD  - Department of Pharmacology and Toxicology, Karl-Franzens-University Graz, A-8010 
      Graz, Austria.
FAU - Malli, Roland
AU  - Malli R
FAU - Schmidt, Kurt
AU  - Schmidt K
FAU - Graier, Wolfgang F
AU  - Graier WF
FAU - Groschner, Klaus
AU  - Groschner K
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 (1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one)
RN  - 0 (Diethylamines)
RN  - 0 (Nitric Oxide Donors)
RN  - 0 (Nitrogen Oxides)
RN  - 0 (Oxadiazoles)
RN  - 0 (Quinoxalines)
RN  - 14691-52-2 (Peroxynitrous Acid)
RN  - 24GP945V5T (Barium)
RN  - 31356-94-2 (8-bromocyclic GMP)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 5O5U71P6VQ (linsidomine)
RN  - 67526-95-8 (Thapsigargin)
RN  - 92818-79-6 (diethylamine dinitric oxide adduct)
RN  - D46583G77X (Molsidomine)
RN  - H2D2X058MU (Cyclic GMP)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Barium/metabolism
MH  - Calcium/*metabolism
MH  - Cell Line
MH  - Cyclic GMP/*analogs & derivatives/pharmacology
MH  - Diethylamines/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Intracellular Membranes/drug effects/physiology
MH  - Membrane Potentials/drug effects
MH  - Mitochondria/*drug effects/metabolism/physiology
MH  - Molsidomine/*analogs & derivatives/pharmacology
MH  - Nitric Oxide/*pharmacology
MH  - Nitric Oxide Donors/*pharmacology
MH  - Nitrogen Oxides
MH  - Oxadiazoles/pharmacology
MH  - Oxygen Consumption/drug effects
MH  - Peroxynitrous Acid/pharmacology
MH  - Quinoxalines/pharmacology
MH  - Thapsigargin/pharmacology
MH  - Time Factors
PMC - PMC1573569
EDAT- 2002/11/02 04:00
MHDA- 2003/04/09 05:00
PMCR- 2003/11/01
CRDT- 2002/11/02 04:00
PHST- 2002/11/02 04:00 [pubmed]
PHST- 2003/04/09 05:00 [medline]
PHST- 2002/11/02 04:00 [entrez]
PHST- 2003/11/01 00:00 [pmc-release]
AID - 0704949 [pii]
AID - 10.1038/sj.bjp.0704949 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2002 Nov;137(6):821-30. doi: 10.1038/sj.bjp.0704949.