Functional Metabotropic Glutamate Receptors on Nuclei from Brain and Primary Cultured Striatal Neurons

Abstract

G-protein-coupled receptors are well known for converting an extracellular signal into an intracellular response. Here we showed that the metabotropic glutamate receptor 5 (mGlu5) plays a dynamic intracellular role in signal transduction. Activation of endogenously expressed mGlu5 on striatal nuclear membranes leads to rapid, sustained calcium (Ca 2؉ ) responses within the nucleoplasm that can be blocked by receptor-specific antagonists. Extracellular ligands such as glutamate and quisqualate reach nuclear receptors via both sodiumdependent transporters and cystine glutamate exchangers. Inhibition of either transport system blocks radiolabeled agonist uptake as well as agonist-induced nuclear Ca 2؉ changes. can enter the nucleoplasm via the nuclear pore complex or from the nuclear lumen, the presence of nuclear mGlu5 receptors appeared to amplify the latter process generating a faster nuclear response in heterologous cells. In isolated striatal nuclei, nuclear receptor activation results in the de novo appearance of phosphorylated CREB protein. Thus, activation of nuclear mGlu5 receptors initiates a signaling cascade that is known to alter gene transcription and regulate many paradigms of synaptic plasticity. These studies demonstrated that mGlu5 receptors play a dynamic role in signaling both on and off the plasma membrane.The structure and function of G-protein-coupled receptors have received intense scrutiny over the past decades. These studies point to a dynamic environment in which receptors are not static but rather move on and off the plasma membrane according to environmental stimuli, specific targeting information, protein-protein interactions, etc. In this model, intracellular receptors are considered transitional, i.e. receptors that are either ready to be inserted into the plasma membrane or that have just been sequestered from such a site. Emerging data, however, suggest that some intracellular receptors may have intracellular functions as well. For example, a number of G-protein-coupled receptors such as the apelin, angiotensin AT1 and ATII, bradykinin B2, and lysophosphatidate LP1 receptors have been localized within the nucleoplasm itself (1-3). In contrast, prostaglandin E 2 receptors have been found on the nuclear envelope together with their ligand-generating enzymes (4, 5). Similarly, endothelin receptors A and B are also localized to the perinuclear region of cardiac ventricular myocytes where they mediate nuclear Ca 2ϩ levels and activate nuclear protein kinases (6). Finally, we have shown that the metabotropic glutamate receptor, mGlu5, 1 can be expressed on nuclear membranes where it can couple with endogenous signaling components to induce changes in nuclear Ca 2ϩ (7). Because most studies investigating the properties of nuclear receptors have been performed in heterologous cell types with overexpressed receptors, the question arises as to whether such phenomena are physiologically relevant and, in the case of mGlu5, how a ligand such as glutamate has access to this receptor.Widely expre...

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca2+ in adult cardiac myocytes

“…This increase was prevented by a cellpermeable analog of an ETB-selective antagonist, IRL-2500, but not by adding BQ610 and BQ788 to the extracellular medium, thus confirming a direct role of nuclear ETB in regulating nuclear Ca 2+ signalling in intact ventricular myocytes. Other GPCRs found in nuclear membranes have also been show to increase [Ca 2+ ] n including Ang II [18,91], bradykinin B2 [21], prostaglandin E 2 [22][23][24], lysophosphatidic acid type-1 [25,26], and metabotropic glutamate type-5 [92][93][94][95].…”

Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

“…This is interesting given that agonist stimulation of mGlu1/5 receptors leads to rapid desensitization (Contractor et al 1998;Gereau and Heinemann 1998). Another reason for the sustained effects of CDPPB may be that functional mGlu5 receptors have been localized on the nuclear membrane of cortical and midbrain neurons, where their activation increases intranuclear calcium release (Jong et al 2005;O'Malley et al 2003). Such an increase may stimulate signaling pathways and favor changes in gene expression, leading to sustained firing rate activation.…”

An update on nuclear calcium signalling

“…The lumen of the NE is topologically the same as the extracellular space, so the ligand-binding domain of nuclear hormone receptors would be exposed within the NE lumen. It has been proposed that specific transporters allow the uptake of neurotransmitters such as glutamate into the NE, where they can bind to their cognate receptors and activate signalling (Jong et al, 2005). Similarly, receptors for endothelin, angiotensin and prostaglandin, the activation of which can also stimulate Ca 2+ -mobilising pathways, are reportedly expressed on nuclear membranes (Bkaily et al, 2006;Coffey et al, 1997).…”