Striatal medium spiny neurons (MSNs) receive glutamatergic afferents from the cerebral cortex and dopaminergic inputs from the substantia nigra (SN). Striatal dopamine loss decreases the number of MSN dendritic spines. This loss of spines has been suggested to reflect the removal of tonic dopamine inhibitory control over corticostriatal glutamatergic drive, with increased glutamate release culminating in MSN spine loss. We tested this hypothesis in two ways. We first determined in vivo if decortication reverses or prevents dopamine depletion--induced spine loss by placing motor cortex lesions 4 weeks after, or at the time of, 6-hydroxydopamine lesions of the SN. Animals were sacrificed 4 weeks after cortical lesions. Motor cortex lesions significantly reversed the loss of MSN spines elicited by dopamine denervation; a similar effect was observed in the prevention experiment. We then determined if modulating glutamate release in organotypic cocultures prevented spine loss. Treatment of the cultures with the mGluR2/3 agonist LY379268 to suppress corticostriatal glutamate release completely blocked spine loss in dopamine-denervated cultures. These studies provide the first evidence to show that MSN spine loss associated with parkinsonism can be reversed and point to suppression of corticostriatal glutamate release as a means of slowing progression in Parkinson's disease.
G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. We report here that genetic deletion of p90 ribosomal S6 kinase 2 (RSK2) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT) 2A receptor signaling in fibroblasts obtained from RSK2 wild-type (؉͞؉) and knockout (؊͞؊) mice showed that 5-HT 2A receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1͞2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, 1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2؊͞؊ fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a ''tonic brake'' on GPCR signal transduction. Our results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase͞ mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations.serotonin ͉ signal transduction G protein-coupled receptors (GPCRs) represent proximal molecular targets for most neurotransmitters, many psychiatric medications, and some drugs of abuse (1). Thus, for instance, antipsychotic and antidepressant medications interact with literally dozens of GPCRs (2). Drugs of abuse tend to have a more restricted pattern of interaction, with morphine being selective for -opioid receptors, and salvinorin A being selective for -opioid sites (3). GPCRs can also function as coreceptors for viruses; thus, the 5-hydroxytryptamine (5-HT) 2A serotonin receptor acts as a coreceptor for the JC virus, the agent responsible for progressive multifocal leukoencepalpathy (4). Agonist-induced activation of GPCRs frequently leads to a complex cascade of intracellular signaling involving arrestins and members of the mitogen-activated protein kinase (MAPK) cascade (5).The p90 ribosomal S6 kinases (RSK)1-4 are downstream members of the extracellular signal-regulated kinase (ERK)͞MAPK cascade, which contain two separate kinase domains connected by a linker domain (Fig. 1B) (6). Multiple phosphorylation events by upstream protein kinases are necessary for the complete activation of the N-terminal kinase (NTK) domain of RSKs (Fig. 1B). The NTK of RSK2 phosphorylates a broad range of substrates, including cAMP r...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.