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  • The distribution and subcellular localization differs betwee

    2024-07-08

    The distribution and subcellular localization differs between the subtypes of mGlu receptors. Most mGlu receptors are broadly expressed in the brain, except for mGlu6, which is restricted to the retina. Some mGlu receptors are additionally found in glial cells, such as mGlu3 and mGlu5 (Aronica et al., 2003; Schools and Kimelberg, 1999). Group I mGlu receptors are mainly localized at postsynaptic sites, whereas Group II and Group III receptors are preferentially expressed in presynaptic axon terminals. Group II mGlu receptors are located away from the glutamate release sites, whereas Group III mGlu receptors are typically localized at the presynaptic active zones (Pinheiro and Mulle, 2008; Shigemoto et al., 1997). This review focuses on the mechanisms that regulate mGlu receptor trafficking, including phosphorylation, protein interactions, and differential endocytic sorting and degradation. As with other GPCRs, second messenger-dependent protein kinases, such as PKA, PKC, and Ca2+/calmodulin-dependent protein kinase II (CaMKII), contribute to Oseltamivir and desensitization. Receptor phosphorylation additionally regulates binding to cytosolic proteins via their CTDs or intracellular loop (iL) domains (Dhami and Ferguson, 2006; Ritter and Hall, 2009). In this review, we discuss the current literature on mGlu receptor-specific binding partners that modulate surface expression and signaling.
    Group I mGlu receptors Group I mGlu receptors (mGlu1 and mGlu5) are Gαq-linked GPCRs, and binding of glutamate triggers a sequence of events: activation of Gαq/11 proteins leading to PLC activity that generates inositol 1,4,5–trisphosphate (IP3) and diacyl glycerol (DAG). IP3 binds to IP3 receptors leading to the release of intracellular Ca2+ from smooth endoplasmic reticulum (SER). DAG activates transient receptor potential Oseltamivir canonical (TRPC)-mediated currents. Simultaneous binding of elevated Ca2+ and DAG activates PKC. mGlu1 and 5 are primarily expressed in the CNS and have distinct and sometimes overlapping distributions in different subtypes of neurons. Group I mGlu receptors are postsynaptic and are located in perisynaptic regions of the postsynaptic membrane of excitatory neurons. mGlu1 and mGlu5 receptors share about 70% sequence homology, and also share many conserved signaling pathways and trafficking routes. There are many factors that have an impact on the trafficking of Group I mGlu receptors.
    Group II and III mGlu receptors Activation of either Group II or III mGlu receptors inhibits AC activity via PTX-sensitive Gi/o, which leads to the inhibition of forskolin-stimulated cAMP formation, and activates the MAPK-ERK pathway. Although these receptors share a common signaling pathway, they differ in their expression patterns and subcellular distribution. For example, mGlu3 and mGlu7 are widely expressed (Ferraguti and Shigemoto, 2006), whereas mGlu6 is restricted to the retina. Group II and Group III mGlu receptors are known substrates for phosphorylation, both the second messenger-dependent protein kinases and GRKs, and phosphorylation affects receptor signaling and desensitization (reviewed in (Iacovelli et al., 2013)). However, very few studies demonstrate clear effects of phosphorylation on trafficking, with the exception of mGlu7. In this section we will discuss trafficking of Group II and III mGlu receptors with a major focus on the mechanisms underlying synaptic expression and endocytosis of mGlu7 (Table 2).
    Conclusion
    Introduction The GABAB receptor agonist (±)baclofen (β p-chlorophenyl-GABA)(Lioresal) is the drug of choice for spasticity in multiple sclerosis and spinal injury and it is also used as analgesic for chronic pain associated with spinal cord injury and trigeminal neuralgia. Baclofen's side effects such as sedation and motor impairment limit its systemic use, and intrathecal delivery is an alternative route of administration which also overcomes baclofen's poor brain penetration (Bowery, 2006).