title: Proteolytic regulation of the mitochondrial cAMP-dependent protein kinase.
abstract: The mitochondrial cAMP-dependent protein kinase (PKA) is activatable in a cAMP-independent fashion. The regulatory (R) subunits of the PKA holoenzyme (R(2)C(2)), but not the catalytic (C) subunits, suffer proteolysis upon exposure of bovine heart mitochondria to digitonin, Ca(2+), and a myriad of electron transport inhibitors. Selective loss of both the RI- and RII-type subunits was demonstrated via Western blot analysis, and activation of the C subunit was revealed by phosphorylation of a validated PKA peptide substrate. Selective proteolysis transpires in a calpain-dependent fashion as demonstrated by exposure of the R and C subunits of PKA to calpain and by attenuation of R and C subunit proteolysis in the presence of calpain inhibitor I. By contrast, exposure of mitochondria to cAMP fails to promote R subunit degradation, although it does result in enhanced C subunit catalytic activity. Treatment of mitochondria with electron transport chain inhibitors rotenone, antimycin A, sodium azide, and oligomycin, as well as an uncoupler of oxidative phosphorylation, also elicits enhanced C subunit activity. These results are consistent with the notion that signals, originating from cAMP-independent sources, elicit enhanced mitochondrial PKA activity.
authors.affiliation: Departments of Chemistry, Chemical Biology and Medicinal Chemistry, and Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, United States.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Shell
authors.forename: David S
authors.initials: DS
authors.lastname: Lawrence
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism; D059748:Proteolysis
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases