Abstract
Large increases in cytosolic free Ca2+ ([Ca2+]i) activate several kinases that are important for neuronal plasticity, including Ca2+/calmodulin-dependent kinase II (CaMKII), protein kinase A (PKA), and protein kinase C (PKC). Because it is also known, mainly in non-neuronal systems, that superoxide radicals (O2-) activate these (and other) kinases and because O2- generation by mitochondria is in part [Ca2+]i dependent, we examined in hippocampal neurons the relationship between Ca2+ entry, O2- production, and kinase activity. We found that, after large stimulus-induced [Ca2+]i increases, O2- selectively produced by mitochondria near plasmalemmal sites of Ca2+ entry acts as a modulator to upregulate the two kinases, namely, CaMKII and PKA, whose activities are directly or indirectly phosphorylation dependent. The common mechanism involves O2- inhibition of inactivating protein phosphatases. Conversely, because small [Ca2+]i increases do not promote mitochondrial respiration and O2- generation, weak stimuli favor enhanced phosphatase activity, which therefore leads to suppressed kinase activity. Enhanced O2- production also promoted PKC activity but by a phosphatase-independent pathway. These results suggest that Ca2+-dependent upregulation of mitochondrial O2- production may be a general mechanism for linking Ca2+ entry to enhanced kinase activity and therefore to synaptic plasticity. This mechanism also represents yet another way that mitochondria, acting as calcium sensors, can play a role in neuronal signal transduction.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Calcium / pharmacology*
-
Calcium Signaling / physiology*
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2
-
Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
-
Cells, Cultured / drug effects
-
Cells, Cultured / metabolism
-
Cyclic AMP-Dependent Protein Kinases / metabolism*
-
Egtazic Acid / analogs & derivatives*
-
Egtazic Acid / pharmacology
-
Enzyme Activation / drug effects
-
Gene Expression Regulation / drug effects*
-
Gene Expression Regulation / physiology
-
Hippocampus / cytology
-
Hippocampus / drug effects*
-
Hippocampus / metabolism
-
Mitochondria / drug effects*
-
Mitochondria / metabolism
-
Neuronal Plasticity / drug effects*
-
Neuronal Plasticity / physiology
-
Neurons / drug effects
-
Neurons / metabolism
-
Okadaic Acid / pharmacology
-
Oligomycins / pharmacology
-
Phosphoprotein Phosphatases / physiology
-
Phosphorylation / drug effects
-
Protein Kinase C / metabolism*
-
Protein Processing, Post-Translational / drug effects
-
Protein Transport / drug effects
-
Rats
-
Rats, Sprague-Dawley
-
Recombinant Fusion Proteins / physiology
-
Rotenone / pharmacology
-
Superoxide Dismutase / genetics
-
Superoxide Dismutase / physiology
-
Superoxides / metabolism*
-
Tetrodotoxin / pharmacology
-
Transfection
Substances
-
Oligomycins
-
Recombinant Fusion Proteins
-
Rotenone
-
Superoxides
-
Okadaic Acid
-
Tetrodotoxin
-
Egtazic Acid
-
Superoxide Dismutase
-
Cyclic AMP-Dependent Protein Kinases
-
Protein Kinase C
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2
-
Calcium-Calmodulin-Dependent Protein Kinases
-
Phosphoprotein Phosphatases
-
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid
-
Calcium