Structural and functional aspects of G protein-coupled receptor oligomerization

Abstract

G protein-coupled receptors (GPCRs) represent the single largest family of cell surface receptors involved in signal transduction. It is estimated that several hundred distinct members of this receptor family in humans direct responses to a wide variety of chemical transmitters, including biogenic amines, amino acids, peptides, lipids, nucleosides, and large polypeptides. These transmembrane receptors are key controllers of such diverse physiological processes as neurotransmission, cellular metabolism, secretion, cellular differentiation, and growth as well as inflammatory and immune responses. GPCRs therefore represent major targets for the development of new drug candidates with potential application in all clinical fields. Many currently used therapeutics act by either activating (agonists) or blocking (antagonists) GPCRs. Studies over the past two decades have provided a wealth of information on the biochemical events underlying cellular signalling by GPCRs. However, our understanding of the molecular interactions between ligands and the receptor protein and, particularly, of the structural correlates of receptor activation or inhibition by agonists and inverse agonists, respectively, is still rudimentary. Most of the work in this area has focused on mapping regions of the receptor responsible for drug binding affinity. Although binding of ligand molecules to specific receptors represents the first event in the action of drugs, the efficacy with which this binding is translated into a physiological response remains the only determinant of therapeutic utility. In the last few years, increasing evidence suggested that receptor oligomerization and in particular dimerization may play an important role in the molecular events leading to GPCR activation. In this paper, we review the biochemical and functional evidence supporting this notion.

Tetraspan Protein CD151 A Common Target of Mood Stabilizing Drugs?

“…LZ motifs mediate dimer formation via a coiled-coil arrangement of parallel ␣-helices, and are found in many eukaryotic transcription factors (Landschulz et al 1988). Although it is well established that many cell surface receptors mediate their action as dimers (Hebert and Bouvier 1998), it remains to be determined whether CD151 exists and functions as homodimer.…”

“…LZ motifs mediate dimer formation via a coiled-coil arrangement of parallel ␣-helices, and are found in many eukaryotic transcription factors (Landschulz et al 1988). Although it is well established that many cell surface receptors mediate their action as dimers (Hebert and Bouvier 1998), it remains to be determined whether CD151 exists and functions as homodimer.Although the precise function of CD151 in the brain has not yet been defined, studies in haemopoietic cell lines have indicated an important role of CD151 in an array of fundamental cellular processes, including cell motility (Yauch et al 1998), cell adhesion (Fitter et al 1999, angiogenesis, and vesicular transport of integrins ). In addition, CD151 has been shown to serve as an adaptor or scaffolding protein to attach integrin subunits to other intracellular signaling molecules, such as phosphatidylinositol 4-kinase (PI 4-K) (Yauch et al 1998) and ␣-and ␤-isozymes of protein kinase C (PKC) (Hemler 1998).…”

Selective stimulation of somatostatin receptor subtypes: differential effects on Ras/MAP kinase pathway and cell proliferation in human neuroblastoma cells

“…The formation of dimers for tyrosine kinase receptors is well assessed but it has only recently been proposed for G proteincoupled receptors (for a review and a comment see [14,15]). Recent evidence that some members of the SSTRs family undergo heterodimerization [16] is in line with our result.…”

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…Data from microscopy, covalent cross-linking, and x-ray crystallography experiments have revealed that cell surface receptors from many structural classes assemble into multi-receptor complexes; these include some heptahelical G-protein coupled receptors (GPCRs), [36][37][38] methyl-accepting chemotaxis proteins (MCPs), [39] gated ion channels, [40] receptor protein tyrosine kinases (RPTKs), [41,42] and multichain immune recognition receptors (MIRRs). [22,33,35,[43][44][45] The size of these ensembles varies: Some complexes are composed of two receptors while others contain thousands.…”

“…[49] For example, helix-mediated multimerization is proposed to mediate the dimerization and oligomerization of GPCRs (Figure 2). [38,50,51] Evidence for the functional importance of these interactions is suggested by engineering disrupting mutations in the proposed contact sites or by adding isolated transmembrane helices to GPCRs. [37,52,53] Although their effects on receptor oligomerization are not yet well-established, these manipulations modulate signaling; presumably, they disrupt receptor-receptor contacts.…”