Protein kinase C inhibits Ca sup 2+ accumulation in cardiac sarcoplasmic reticulum
- Univ. of Maryland School of Medicine, Baltimore (USA)
It is now recognized that phorbol esters are negative inotropic agents in mammalian heart which presumably act via stimulation of Ca2(+)-activated phospholipid-dependent protein kinase (PKC). The goal in the present study was to identify the underlying cellular processes. Digitonin-permeabilized cultured neonatal rat ventricular myocytes were used to study biochemical and functional effects of phorbol esters on cardiac sarcoplasmic reticulum (SR). These cells contracted spontaneously at 3 microM Ca2+. Beating was inhibited by 10 microM ryanodine and was insensitive to 1 microM nifedipine. Thus, beating behavior results from the phasic oscillation of Ca2+ transport by SR in this preparation. Phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), decreased frequency by 30%, suggesting that Ca2+ transport by SR had been reduced. Whereas cAMP stimulated the rate of oxalate-supported 45Ca2+ uptake 2-fold, phorbol esters, TPA, and phorbol 12,13-dibutyrate inhibited this process by about 45%. The effects of phorbols were specific: (a) the alpha-analogues of TPA and phorbol 12,13-dibutyrate were inactive; and (b) the phorbol esters had no effect on Ca2+ transport in cells that had been depleted of PKC. TPA decreased oxalate-stimulated Ca2+ uptake over the entire range of Ca2+ concentrations, from 0.1 to 10 microM, by at least 70% without shifting the half-maximal effective Ca2+ concentration. Taken together these results indicate that the effects of phorbol ester on cardiac contraction are due to decreased Ca2+ transport by the SR and that these responses are mediated by PKC. These studies support the interpretation that the negative inotropic effects of phorbol esters are due, in part, to decreased SR function.
- OSTI ID:
- 6967331
- Journal Information:
- Journal of Biological Chemistry; (USA), Journal Name: Journal of Biological Chemistry; (USA) Vol. 265:8; ISSN JBCHA; ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- English
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560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKALINE EARTH ISOTOPES
ALKALINE EARTH METAL COMPOUNDS
AMP
ANIMALS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL EFFECTS
BODY
CALCIUM 45
CALCIUM COMPOUNDS
CALCIUM ISOTOPES
CARCINOGENS
CARDIOVASCULAR SYSTEM
CELL CONSTITUENTS
CELL CULTURES
CELL MEMBRANES
CONTRACTION
DAYS LIVING RADIOISOTOPES
ENDOPLASMIC RETICULUM
ENZYMES
ESTERS
EVEN-ODD NUCLEI
HEART
INTERMEDIATE MASS NUCLEI
ISOTOPE APPLICATIONS
ISOTOPES
KINETICS
MAMMALS
MEMBRANE TRANSPORT
MEMBRANES
MUSCLES
MYOCARDIUM
NEONATES
NUCLEI
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANOIDS
ORGANS
PHORBOL ESTERS
PHOSPHORUS-GROUP TRANSFERASES
PHOSPHOTRANSFERASES
RADIOISOTOPES
RATS
REACTION KINETICS
RODENTS
SARCOPLASMIC RETICULUM
TRACER TECHNIQUES
TRANSFERASES
VERTEBRATES