G Protein-Coupled Receptor Signaling Complexity in Neuronal Tissue:Implications for Novel Therapeutics

Abstract

The manipulation of transmembrane signaling by G protein-coupled receptors (GPCRs) constitutes perhaps the single most important therapeutic target in medicine. Therapeutics acting on GPCRs have traditionally been classified as agonists, partial agonists, or antagonists based on a two state model of receptor function embodied in the ternary complex model. Over the past decade, however, many lines of investigation have shown that GPCR signaling exhibits greater diversity and 'texture' than previously appreciated. Signal diversity arises from numerous factors, among them the ability of receptors to adopt multiple 'active' states with different effector coupling profiles, the formation of receptor dimers that exhibit unique pharmacology, signaling, and trafficking, the dissociation of receptor 'activation' from desensitization and internalization, and the discovery that non-G protein effectors mediate some aspects of GPCR signaling. At the same time, clustering of GPCRs with their downstream effectors in membrane microdomains, and interactions between receptors and a plethora of multidomain scaffolding proteins and accessory/chaperone molecules confers signal preorganization, efficiency, and specificity. More importantly it is likely that alteration in the interactions of these proteins with GPCRs may occur in aging or neurodegenerative disorders, thus defining a distinct 'pharmacology' from that seen in young organisms or normal physiology. In this context, the concept of agonist selective trafficking of receptor signaling, which recognizes that a bound ligand may select between a menu of 'active' receptor conformations and induce only a subset of the possible response profile, presents the opportunity to develop drugs that change the quality as well as the quantity of efficacy and enhance these qualities for specific disorders or other paradigms. As a more comprehensive understanding of the complexity of GPCR signaling is developed, the rational design of ligands possessing increased specific efficacy and attenuated side effects may become the standard mode of drug development.

Growth Factor Signals in Neural Cells

“…Extracellular signals, such as hormones, neurotransmitters, and growth factors, regulate a wide variety of cellular activities, including neuronal excitation, cell survival, growth, and differentiation. Intracellular transduction systems receive these signals via receptors and transmit them to the ligand-prescribed cell compartment quickly and precisely, resulting in the amplification of specific biological responses (43,44). However, cells are often exposed to several stimulating ligands and maintaining the fidelity of the signaling networks is crucial in eliciting the appropriate physiological response.…”

“…Organizing this requires the accurate selection of effector molecules for regulated activation and deactivation, often by phosphorylation and dephosphorylation events. A principal strategy in achieving this selection specificity is compartmentalization of signaling enzymes (43). Another signaling mechanism that we have recently described (45,46) is the creation of discrete signaling microcomplexes linked to transmembrane receptors, such as G protein-coupled receptors, that are able to then translocate to different cell compartments after separating from the cell surface receptor and then effectively transmit a unique signal depending upon the nature of the initial receptor stimulation.…”

The Mammalian Tachykinin Ligand-Receptor System: An Emerging Target for Central Neurological Disorders

“…AD is one of most prevalent diseases in Westernized countries, and an efficacious treatment strategy represents one of the most important challenges in modern medicine [79, 80]. The physiological mechanisms leading to the generation of AD pathophysiology are complex and multifactorial [81–83].…”

Mechanisms of dominant negative G‐protein α subunits

“…GPCRs and G-proteins are widely distributed throughout the CNS and play a major role in the regulation of neuronal activity and behavior (Karasinska et al, 2003;Maudsley et al, 2007). Furthermore, extensive cross-talk between GPCR-mediated signaling and receptor tyrosine kinases in the CNS leads to transactivation of RTKs, thus contributing to the regulation of neuronal development, proliferation, differentiation, survival, repair, migration, and synaptic transmission (Shah and Catt, 2004).…”