The interaction between mGluR1 and the calcium channel CaV2.1 preserves coupling in the presence of long Homer proteins
University of Rochester Medical Center, Department of Pharmacology and Physiology, Rochester, NY 14642, USA.Neuropharmacology (Impact Factor: 5.11). 05/2012; 66. DOI: 10.1016/j.neuropharm.2012.05.038
Group I metabotropic glutamate receptors (mGluR1 and 5) are G protein coupled receptors that regulate neuronal activity in a number of ways. Some of the most well studied functions of group I mGluRs, such as initiation of multiple forms of mGluR-dependent long-term depression, require receptor localization near the post-synaptic density (PSD). This localization is in turn dependent on the Homer family of scaffolding proteins which bind to a small motif on the distal C-termini of mGluR1 and 5, localize the receptors near the PSD, strengthen coupling to post-synaptic effectors and simultaneously uncouple the mGluRs from extra-synaptic effectors such as voltage dependent ion channels. Here the selectivity of this uncoupling process was examined by testing the ability of Homer-2b to uncouple mGluR1 from multiple voltage dependent calcium channels including Ca(V2.2) (N-type), Ca(V3.2) (T-type), and Ca(V2.1) (P/Q-type) expressed in rat sympathetic neurons from the superior cervical ganglion (SCG). Of these, only the mGluR1-Ca(V2.1) modulatory pathway was insensitive to Homer-2b expression. Uncoupling from this channel was achieved by co-expression of an mGluR1 C-terminal protein designed to disrupt a previously described direct interaction between these two proteins, suggesting that this interaction allows incorporation of Ca(V2.1) into the mGluR1/Homer signaling complex, thereby preserving modulation in the presence of scaffolding Homer proteins. This article is part of a Special Issue entitled 'mGluR'.
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ABSTRACT: While group 1 metabotropic glutamate receptors (mGluRs) and ionotropic N-methyl-D-aspartate (NMDA) receptors regulate nociception, the precise molecular mechanism(s) contributing to glutamate signaling in chronic pain remain unclear. Here we not only confirmed the key involvement of Homer proteins in neuropathic pain, but also distinguished between the functional roles for different Homer family members and isoforms. Chronic constriction injury (CCI) of the sciatic nerve induced long-lasting, time-dependent increases in the postsynaptic density expression of the constitutively expressed (CC) isoforms Homer1b/c and/or Homer2a/b in the spinal dorsal horn and supraspinal structures involved in nociception (prefrontal cortex, thalamus), that co-occurred with increases in their associated mGluRs, NR2 sub-units of the NMDA receptor, and the activation of downstream kinases. Virus-mediated overexpression of Homer1c and Homer2b after spinal (intrathecal) virus injection exacerbated CCI-induced mechanical and cold hypersensitivity, however, Homer1 and Homer2 gene knockout (KO) mice displayed no changes in their neuropathic phenotype. In contrast, overexpression of the immediate early gene (IEG) Homer1a isoform reduced, while KO of Homer1a gene potentiated neuropathic pain hypersensitivity. Thus, nerve injury-induced increases in CC-Homers expression promote pain in pathological states, but IEG-Homer induction protects against both the development and maintenance of neuropathy. Additionally, exacerbated pain hypersensitivity in transgenic mice with reduced Homer binding to mGluR5 supports also an inhibitory role for Homer interactions with mGluR5 in mediating neuropathy. Such data indicate that nerve injury-induced changes in glutamate receptor/Homer signaling contribute in dynamic but distinct ways to neuropathic pain processing, which has relevance for the etiology of chronic pain symptoms and its treatment.Pain 04/2013; 154(10). DOI:10.1016/j.pain.2013.03.035 · 5.21 Impact Factor
Article: Homer Proteins in Ca2+ Entry[Show abstract] [Hide abstract]
ABSTRACT: The Homer family of proteins consists of three adaptor proteins, Homer1, Homer2 and Homer3, each with various isoforms. Homer1 family presents an EVH1 domain, a coiled coil domain and two leucine zipper domains. Homer proteins regulate a number of Ca2+-handling proteins, including transient receptor potential channels and other Ca2+-permeable channels, ionotropic and metabotropic glutamate receptors, shank scaffolding proteins or endoplasmic reticulum Ca2+ release channels. This review article focuses on the association of Homer 1 proteins with Ca2+-handling proteins and their role on intracellular Ca2+-homeostasis. © 2013 IUBMB Life.International Union of Biochemistry and Molecular Biology Life 04/2013; 65(6). DOI:10.1002/iub.1162 · 3.14 Impact Factor
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ABSTRACT: Homer postsynaptic scaffolding proteins regulate forebrain glutamate transmission and thus, are likely molecular candidates mediating hypofrontality in addiction. Protracted withdrawal from cocaine experience increases the relative expression of Homer2 versus Homer1 isoforms within medial prefrontal cortex (mPFC). Thus, this study used virus-mediated gene transfer strategies to investigate the functional relevance of an imbalance in mPFC Homer1/2 expression as it relates to various measures of sensorimotor, cognitive, emotional and motivational processing, as well as accompanying alterations in extracellular glutamate in C57BL/6J mice. mPFC Homer2b overexpression elevated basal glutamate content and blunted cocaine-induced glutamate release within the mPFC, whereas Homer2b knockdown produced the opposite effects. Despite altering mPFC glutamate, Homer2b knockdown failed to influence cocaine-elicited conditioned place preferences, nor did it produce consistent effects on any other behavioral measures. In contrast, elevating the relative expression of Homer2b versus Homer1 within mPFC, by overexpressing Homer2b or knocking down Homer1c, shifted the dose-response function for cocaine-conditioned reward to the left, without affecting cocaine locomotion or sensitization. Intriguingly, both these transgenic manipulations produced glutamate anomalies within the nucleus accumbens (NAC) of cocaine-naive animals that are reminiscent of those observed in cocaine experienced animals, including reduced basal extracellular glutamate content, reduced Homer1/2 and glutamate receptor expression, and augmented cocaine-elicited glutamate release. Together, these data provide novel evidence in support of opposing roles for constitutively expressed Homer1 and Homer2 isoforms in regulating mPFC glutamate transmission in vivo and support the hypothesis that cocaine-elicited increases in the relative amount of mPFC Homer2 versus Homer1 signaling produces abnormalities in NAC glutamate transmission that enhance vulnerability to cocaine reward.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 05/2013; 33(19):8101-13. DOI:10.1523/JNEUROSCI.1727-12.2013 · 6.34 Impact Factor
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