| First Author | Yang L | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 14 | Pages | 4896-904 |
| PubMed ID | 24695708 | Mgi Jnum | J:208122 |
| Mgi Id | MGI:5561144 | Doi | 10.1523/JNEUROSCI.3460-13.2014 |
| Citation | Yang L, et al. (2014) Selective Expression of a Dominant-Negative Type Ialpha PKA Regulatory Subunit in Striatal Medium Spiny Neurons Impairs Gene Expression and Leads to Reduced Feeding and Locomotor Activity. J Neurosci 34(14):4896-904 |
| abstractText | 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 RIIbeta, which localizes the PKA holoenzyme primarily to dendrites by interaction with AKAP5 and other scaffolding proteins. However, RI (RIalpha and RIbeta) 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 (RIalphaB) in striatal MSNs and show that this dominant-negative RIalphaB 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 RIalphaB-expressing mice also exhibit decreased locomotor activity and decreased dopamine-regulated CREB phosphorylation and c-fos gene 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. |
