Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor

Abstract

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This license does not permit commercial exploitation or the creation of derivative works without specific permission.G-protein-coupled receptors (GPCRs) respond to external stimuli by activating heterotrimeric G proteins inside the cell. There is increasing evidence that many GPCRs exist as dimers or higher oligomers, but the biochemical nature of such dimers and what roles they have, if any, in signal transduction remains unclear. We conducted a comprehensive study of dimerization of the 5HT2c serotonin receptor using disulphide-trapping experiments. We found a dimer interface between transmembrane (TM) helices IV and V that is markedly sensitive to the state of receptor activation. This dimer seems to be quasisymmetrical in interfacial geometry and asymmetrical in its association with its cognate Ga protein. We also found a second interface at TM I helices, which is insensitive to the state of activation.

Light on the structure of thromboxane A2 receptor heterodimers

“…This is consistent with emerging evidence from structure determinations, structure predictions and in vitro experiments on homologous GPCRs, suggesting that H1 is likely to be a privileged mediator of dimerization/oligomerization of these membrane proteins [15,16,23,24,27,28,32]. The architecture of the predicted TP dimers is such that it is likely shared by both TPa and TPb homodimers as well as TPa-TPb heterodimers.…”

“…The involvement of H1/H8 GPCR oligomerization has been recently proposed for the b 2 -AR as well [15]. Finally, recent in vitro disulphide-trapping experiments on the 5HT 2c receptor suggest the existence of dimer architectures insensitive and sensitive to the functional states of the receptor [27]. In this respect, state-insensitive architectures would involve H1-H1 contacts, whereas state-sensitive architectures would be characterized by H4-H5 contacts [27].…”

“…Finally, recent in vitro disulphide-trapping experiments on the 5HT 2c receptor suggest the existence of dimer architectures insensitive and sensitive to the functional states of the receptor [27]. In this respect, state-insensitive architectures would involve H1-H1 contacts, whereas state-sensitive architectures would be characterized by H4-H5 contacts [27]. Collectively, consensus emerges on H1, H4 and H5 being involved in GPCR dimerization/oligomerization.…”

“…System's dependent variety in the dimer architecture emerges also from results of in vitro experiments. In this respect, the highest resolution information available thus far comes from X-ray crystallography and atomic force microscopy (AFM) measurements on rhodopsin, opsin, b 2 -AR and CXCR4 chemokine receptor, as well as from cysteine crosslinking experiments on D 2 receptor (D 2 R), and disulphide trapping experiments on 5HT 1c receptor [22][23][24][25][26][27][28][29]. With regard to rhodopsin, the geometrical constraints from AFM measurements led to the proposal of a semi-empirical model of a higher order rhodopsin structure [22].…”

Asymmetric perturbations of signalling oligomers

“…Also, allosteric modulators of heterodimeric metabotropic glutamate receptors exert different efficacies depending on which subunit they bind to . Asymmetric activation of 5-HT 2C -type seronin and oxytocin class A GPCRs was also demonstrated with disulphide-trapping and radioligand binding as well as with timeresolved FRET and living cells, respectively (Albizu et al, 2010;Mancia et al, 2008) The growth factor receptor family belongs to tyrosine kinases activated by ligand-induced dimerization. The asymmetric dimerization of epidermal growth factor receptors (EGFRs) has been thoroughly studied via XRC and mutational analysis.…”