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Potential involvement of calcium, CaM kinase II, and MAP kinases in PCB-stimulated insulin release from RINm5F cells. 1999

L J Fischer, and M A Wagner, and B V Madhukar
Department of Pharmacology and Toxicology and Institute for Environmental Toxicology, Michigan State University, East Lansing, Michigan, 48824, USA.

Polychlorinated biphenyls (PCBs) are environmental contaminants that induce release of insulin in rat insulinoma cells, RINm5F (Fischer et al., Life Sci. (1996) 59, 2041-2049). In the present study the mechanisms of this effect were investigated using noncytotoxic concentrations (10 microg/ml) of a PCB mixture, Aroclor-1254, and the pure PCB congeners 2,2',4,4'-tetrachlorobiphenyl and 2,2',4,4',5, 5'-hexachlorobiphenyl. Treatment of RINm5F cells with each of these agents resulted in a rapid increase in intracellular free calcium. The presence of extracellular calcium was required for PCB-induced insulin release because removal of calcium from the medium attenuated the effect. In addition, pretreatment of RINm5F cells with the calcium channel blocker verapamil also blocked PCB-induced insulin release. To determine whether PCB-related insulin release could be associated with the enzyme, calcium/calmodulin-dependent kinase II (CaM kinase II), RINm5F cells were pretreated with the CaM kinase II inhibitor KN-93. PCB-induced insulin release was completely blocked by KN-93. Under similar treatment conditions, PCBs also induced the activity of mitogen-activated protein kinases (MAPK) 1 and 2. However, inhibition of MAPK activation by a specific inhibitor, PD-98059 (10.0 microM) did not prevent insulin release induced by PCBs. The results of the present investigation suggest a role for calcium and CaM kinase II in PCB-induced insulin release. Furthermore, the results suggest that insulin release by PCBs is independent of the activation of MAPKs.

UI MeSH Term Description Entries
D007328 Insulin A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1). Iletin,Insulin A Chain,Insulin B Chain,Insulin, Regular,Novolin,Sodium Insulin,Soluble Insulin,Chain, Insulin B,Insulin, Sodium,Insulin, Soluble,Regular Insulin
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
D011078 Polychlorinated Biphenyls Industrial products consisting of a mixture of chlorinated biphenyl congeners and isomers. These compounds are highly lipophilic and tend to accumulate in fat stores of animals. Many of these compounds are considered toxic and potential environmental pollutants. PCBs,Polychlorinated Biphenyl,Polychlorobiphenyl Compounds,Biphenyl, Polychlorinated,Biphenyls, Polychlorinated,Compounds, Polychlorobiphenyl
D002118 Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Coagulation Factor IV,Factor IV,Blood Coagulation Factor IV,Calcium-40,Calcium 40,Factor IV, Coagulation
D005659 Fungicides, Industrial Chemicals that kill or inhibit the growth of fungi in agricultural applications, on wood, plastics, or other materials, in swimming pools, etc. Industrial Fungicides
D006581 Hexachlorobenzene An agricultural fungicide and seed treatment agent. HCB
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D014407 Tumor Cells, Cultured Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely. Cultured Tumor Cells,Neoplastic Cells, Cultured,Cultured Neoplastic Cells,Cell, Cultured Neoplastic,Cell, Cultured Tumor,Cells, Cultured Neoplastic,Cells, Cultured Tumor,Cultured Neoplastic Cell,Cultured Tumor Cell,Neoplastic Cell, Cultured,Tumor Cell, Cultured
D051381 Rats The common name for the genus Rattus. Rattus,Rats, Laboratory,Rats, Norway,Rattus norvegicus,Laboratory Rat,Laboratory Rats,Norway Rat,Norway Rats,Rat,Rat, Laboratory,Rat, Norway,norvegicus, Rattus
D054732 Calcium-Calmodulin-Dependent Protein Kinase Type 2 A multifunctional calcium-calmodulin-dependent protein kinase subtype that occurs as an oligomeric protein comprised of twelve subunits. It differs from other enzyme subtypes in that it lacks a phosphorylatable activation domain that can respond to CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE. Ca(2+)-Calmodulin Dependent Protein Kinase Type II,CaCMKII,CaM KII,CaM KIIalpha,CaM KIIbeta,CaM KIIdelta,CaM Kinase II,CaM Kinase II alpha,CaM Kinase II beta,CaM Kinase II delta,CaM Kinase II gamma,CaM PK II,CaM-Kinase II,CaM-Kinase IIalpha,CaMKII,CaMKIIgamma,Calcium-Calmodulin Dependent Protein Kinase II beta,Calcium-Calmodulin Dependent Protein Kinase II delta,Calcium-Calmodulin Dependent Protein Kinase II gamma,Calcium-Calmodulin Protein Kinase II,Calcium-Calmodulin-Dependent PK Type II,Calcium-Calmodulin-Dependent Protein Kinase Type 2 alpha Subunit,Calcium-Calmodulin-Dependent Protein Kinase Type 2 beta Subunit,Calcium-Calmodulin-Dependent Protein Kinase Type 2 delta Subunit,Calcium-Calmodulin-Dependent Protein Kinase Type 2 gamma Subunit,Calcium-Dependent CaM Kinase II,Calmodulin Kinase IIalpha,Calmodulin-Dependent Protein Kinase II,CaM Kinase IIalpha,Calcium Calmodulin Dependent PK Type II,Calcium Calmodulin Dependent Protein Kinase II beta,Calcium Calmodulin Dependent Protein Kinase II delta,Calcium Calmodulin Dependent Protein Kinase II gamma,Calcium Calmodulin Dependent Protein Kinase Type 2,Calcium Calmodulin Dependent Protein Kinase Type 2 alpha Subunit,Calcium Calmodulin Dependent Protein Kinase Type 2 beta Subunit,Calcium Calmodulin Dependent Protein Kinase Type 2 delta Subunit,Calcium Calmodulin Dependent Protein Kinase Type 2 gamma Subunit,Calcium Calmodulin Protein Kinase II,Calcium Dependent CaM Kinase II,Calmodulin Dependent Protein Kinase II

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