Targeted disruption of the RI and RII regulatory subunits of the cAMP-dependent protein kinase (PKA) in mice: physiological and neurobiological defects
The cAMP-dependent protein kinase (PKA) mediates the intracellular responses to myriad extracellular signals in eukaryotic organisms. Although the functions of this enzyme have been extensively studied, little is known about the roles of specific isoforms of PKA. In order to determine the roles of the regulatory subunits RI$\beta$ and RII$\beta,$ gene targeting technology was utilized to establish mice that carry null alleles of either the RI$\beta$ or the RII$\beta$ genes.Previous experiments had suggested important roles for PKA in forms of hippocampal synaptic plasticity that may underlie learning in mammals. Both long-term potentiation (LTP) and long-term depression (LTD) were analyzed in the hippocampal slices prepared from mice lacking the RI$\beta$ subunit. No defects were observed in LTP at the Schaffer collateral-CA1 synapse, but a dramatic defect was observed in homosynaptic LTD, suggesting an important role for RI$\beta$ and PKA in this phenomenon.PKA is the downstream effector of several neurotransmitters including dopamine. The dopaminergic projections to the mammalian striatum are important in regulation of motor function including coordination and locomotion. Because RII$\beta$ is expressed at high levels in the striatum, it was hypothesized that this subunit might play a specialized role in dopaminergic signaling. Mice lacking RII$\beta$ were found to have defects in both rotarod performance (a measure of coordination) and activation of locomotion by dopaminergic agonists. Moreover, these mice had changes in both expression of the gene encoding the neuropeptide dynorphin and the induction of the immediate early gene c-fos by amphetamine in the striatum. These results demonstrate that the Type II$\beta$ PKA is a direct mediator of gene induction in response to a dopaminergic agent, and suggest that Type II$\beta$ PKA is responsible for the fine tuning of motor behavior.Lastly, mice lacking RII$\beta$ were found to have reduced adiposity and increased metabolism as measured by oxygen consumption and body temperature. These findings are believed to reflect a functional switch from Type II$\beta$ PKA to Type I$\alpha$ PKA in the adipocytes of these mutants. Collectively, these results begin to elucidate some of the specific roles of the different PKA regulatory subunits in mice.
- Pharmacology