Selective Expression of a Dominant-Negative Type Ια PKA Regulatory Subunit in Striatal Medium Spiny Neurons Impairs Gene Expression and Leads to Reduced Feeding and Locomotor Activity
Copyright policy )Selective Expression of a Dominant-Negative Type Ια PKA Regulatory Subunit in Striatal Medium Spiny Neurons Impairs Gene Expression and Leads to Reduced Feeding and Locomotor Activity
Striatal medium spiny neurons (MSNs) mediate many of the physiological effects of dopamine, including the regulation of feeding and motor behaviors. Dopaminergic inputs from the midbrain modulate MSN excitability through pathways that involve cAMP and protein kinase A (PKA), but the physiological role of specific PKA isoforms in MSN neurons remains poorly understood. One of the major PKA regulatory (R) subunit isoforms expressed in MSNs is RIIβ, which localizes the PKA holoenzyme primarily to dendrites by interaction with AKAP5 and other scaffolding proteins. However, RI (RIα and RIβ) subunits are also expressed in MSNs and the RI holoenzyme has a weaker affinity for most scaffolding proteins and tends to localize in the cell body. We generated mice with selective expression of a dominant-negative RI subunit (RIαB) in striatal MSNs and show that this dominant-negative RIαB localizes to the cytoplasm and specifically inhibits type I PKA activity in the striatum. These mice are normal at birth; however, soon after weaning they exhibit growth retardation and the adult mice are hypophagic, lean, and resistant to high-fat diet-induced hyperphagia and obesity. The RIαB-expressing mice also exhibit decreased locomotor activity and decreased dopamine-regulated CREB phosphorylation and c-fosgene expression in the striatum. Our results demonstrate a critical role for cytoplasmic RI-PKA holoenzyme in gene regulation and the overall physiological function of MSNs.
- University of Washington United States
- University of Mary United States
Neurons, Dopamine and cAMP-Regulated Phosphoprotein 32, Movement Disorders, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Body Weight, Dopamine Agents, Mice, Transgenic, Feeding Behavior, Motor Activity, Corpus Striatum, Enzyme Activation, Mice, Inbred C57BL, Mice, Animals, Newborn, Gene Expression Regulation, Mutation, Cyclic AMP, Animals, Obesity
Neurons, Dopamine and cAMP-Regulated Phosphoprotein 32, Movement Disorders, Cyclic AMP-Dependent Protein Kinase RIalpha Subunit, Body Weight, Dopamine Agents, Mice, Transgenic, Feeding Behavior, Motor Activity, Corpus Striatum, Enzyme Activation, Mice, Inbred C57BL, Mice, Animals, Newborn, Gene Expression Regulation, Mutation, Cyclic AMP, Animals, Obesity
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