Functional differences between D(1) and D(5) revealed by high resolution imaging on live neurons.
ABSTRACT The interaction between the dopaminergic and glutamatergic systems governs normal behavior and is perturbed in many psychiatric disorders including schizophrenia. Hypofunction of the D1 family of receptors, to which the D(1) and D(5) subtypes belong, is a typical feature of schizophrenia. Here we have used confocal live cell imaging of neurons to examine the distinct roles of the D(1) and D(5) receptors in the intra-neuronal interaction with the glutamatergic system. Using fluorescently tagged D(1) or D(5) expressed in cultured striatal neurons, we show that both receptor subtypes are primarily transported via lateral diffusion in the dendritic tree. D(1) is to a much larger extent than D(5) expressed in spines. D(1) is primarily expressed in the head whereas D(5) is largely localized to the neck of the spine. Activation of N-methyl-D-aspartic acid (NMDA) receptors slowed the diffusion rate and increased the number of D(1) positive spines, while no effect on D(5) diffusion or spine localization could be observed. The observed differences between D(1) and D(5) can be attributed to structural differences in the C-terminus and its capacity to interact with NMDA receptors and PSD-95. Identification of a unique role of D(1) for the intra-neuronal interaction between the dopaminergic and glutamatergic systems will have implications for the development of more specific treatments in many neuropsychiatric disorders.
Article: GPCR interacting proteins (GIP).[show abstract] [hide abstract]
ABSTRACT: G protein-coupled receptors (GPCR) interact not only with heterotrimeric G proteins but also with accessory proteins called GPCR interacting proteins (GIP). These proteins have important functions. They are implicated in GPCR targeting to specific cellular compartments, in their assembling into large functional complexes called "receptosomes," in their trafficking to and from the plasma membrane, and in the fine-tuning of their signaling properties. There are several types of GIPs. Some are transmembrane proteins such as another GPCR (homodimerization and heterodimerization), ionic channels, ionotropic receptors, and single transmembrane proteins. The latter is implicated in the fine-tuning of receptor pharmacology or signaling. Other GIPs are soluble proteins interacting mainly with the "magic" C-terminal tail. Among them, PDZ domain-containing proteins are the most abundant. They generally, but not always, interact with the extreme C-terminal domain of GPCRs. Some GIPs interact with specific sequences of the C-terminal such as the Homer binding sequence (-PPxxFR-), the dopamine receptor interacting protein (DRIP) binding sequence (-FxxxFxxxF-), etc. Finally, only few GIPs have been found thus far to interact with the third intracellular loop of GPCRs. The future will tell us if this situation is only due to technical reasons.Pharmacology [?] Therapeutics 10/2004; 103(3):203-21. · 7.79 Impact Factor
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ABSTRACT: Subjects with schizophrenia (SZ) have an increased density of synapses characteristic of corticostriatal or thalamostriatal glutamatergic inputs in the caudate matrix and putamen patches. SZ is a heterogeneous disease in many aspects including symptoms. The purpose of the present study was to determine if the synaptic organization in two different DSM-i.v. subgroups of SZ was differentially affected. Postmortem striatal tissue was obtained from the Maryland Brain Collection from normal controls (NC), chronic paranoid SZs (SZP), and chronic undifferentiated SZs (SZU). Tissue was prepared for calbindin immunocytochemistry to identify patch matrix compartments, prepared for electron microscopy and analyzed using stereological methods. The synaptic density of asymmetric synapses, characteristic of glutamatergic inputs, was elevated equivalently in striatal patches in the SZP and SZU versus NC. The SZU also had an increased density of asymmetric synapses in the striatal matrix compared to NC. Moreover, symmetric axospinous synapses, characteristic of intrinsic inhibitory inputs and dopaminergic afferents, showed a dichotomy in synaptic density between the SZU and SZP in the striatal and caudate matrix. These data show discreet differences in synaptic organization between SZU and SZP and/or NCs. The results suggest that abnormal corticostriatal and/or corticothalamic inputs to striatal patches may be related to limbic dysfunction, which is perturbed in both subtypes of SZ. The selective increase in axospinous synapses in the matrix of the SZU subgroup compared to the SZP may be related to more severe cognitive problems in that subset of SZ compared to SZP.Synapse 09/2008; 62(8):616-27. · 2.31 Impact Factor
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ABSTRACT: As the major components of the postsynaptic density of excitatory neuronal synapses, PDZ-domain-containing scaffold proteins regulate the clustering of surface glutamate receptors, organize synaptic signalling complexes, participate in the dynamic trafficking of receptors and ion channels, and coordinate cytoskeletal dynamics. These scaffold proteins often contain multiple PDZ domains, with or without other protein-binding modules, and they usually lack intrinsic enzymatic activities. Recent biochemical and structural studies have shown that tandemly arranged PDZ domains often serve as structural and functional supramodules that could regulate the organization and dynamics of synaptic protein complexes, thus contributing to the broad range of neuronal activity.Nature Reviews Neuroscience 03/2009; 10(2):87-99. · 26.48 Impact Factor