This special issue, entitled: The changing world of G protein-coupled receptors, is based on a Royal Swedish Academy of Sciences symposium held in Stockholm, Sweden on May 18 2010 organized by Dr K Fuxe under the theme “The changing world of G protein-coupled receptors: From monomers to dimers and receptor mosaics (higher order oligomers)”.
The first section of the issue introduces the GPCR field and its novel terminology. The Kenakin et al. paper summarizes a workshop held on GPCRs, and receptor–receptor interactions and their terminology, held at Nobel Forum, Karolinska Institutet on May 19 2010, during which the definition of the “receptor–receptor interactions” was agreed upon.
The early work on negative cooperativity and neuropeptide-monoamine receptor–receptor interactions in the CNS is reported to give some of the first indications of the existence of homodimers and heterodimers of GPCRs, respectively, and the field began to expand from monomers into dimers and receptor mosaics. It is also emphasized that the existence of receptor heteromers with allosteric receptor–receptor interactions increases the diversity of GPCR recognition and signaling. The molecular phenomenon of receptor–receptor interactions is proposed to give a better understanding of brain function through molecular integration of signals. An alteration in specific receptor–receptor interactions is in fact considered to play a role in pathogenic mechanisms leading to several diseases, inter alia Parkinson’s disease, hypertension, schizophrenia, addiction and depression. Therefore, pharmacological targeting of receptor–receptor interactions in heteromers is described as an important area for developing more selective drugs including bivalent compounds and optimal types of combined treatments.
The second section covers the dynamics of GPCRs. Vilardaga reviews the kinetics of GPCR activation/deactivation including the importance of the associated conformational changes in these processes, and Kenakin reviews the GPCR and their assemblies as representing allosteric systems where the allosteric mechanisms have a major role in determining their pharmacology. He clearly outlines the allosteric modulators of GPCRs as highly valuable therapeutics.
The third section gives the state of the art on GPCR heterodimers and receptor mosaics of different types of GPCRs, and their receptor–receptor interactions. Ciruela et al. report inter alia, the impact of heteromerization on receptor biosynthesis, plasma membrane diffusion or velocity, and pharmacology, and discuss the molecular basis of the receptor interface in the GPCR oligomers. It is underlined that the challenge still remains to give direct evidence for receptor–receptor interactions in heteromers in native tissue. Woods et al. summarize the overall evidence for the importance of electrostatic receptor–receptor interactions in the formation of the receptor interface in GPCR heteromers. Nakata et al. review their evidence for the ability of GPCR heterodimerization to increase the diversity of purinergic signaling via changes in receptor function. Missale et al. bring together the evidence for a putative role of D1-NMDA and D1–D3 heteromers in striatal function. Agnati et al. give an integrated view on the role of receptor mosaics at perisynaptic level with focus on the available evidence for receptor–receptor interactions between adenosine A2A, dopamine D2, cannabinoid CB1, and metabotropic glutamate mGlu5 receptors. The concept of “hub receptor” is defined in accordance with informatics and is tentatively illustrated in the case of the hypothesized tetramer formed by the four receptors in striatopallidal GABA neurons and their glutmate afferents.
We fully appreciate the outstanding quality of the papers received for this special issue and hope that the readers of the Journal of Receptors and Signal Transduction will find them of special value. Increasing our understanding of molecular integration of signals via allosteric receptor–receptor interactions in GPCR dimers and receptor mosaics will have an impact on molecular medicine leading to novel strategies for treatment, and finally novel drugs for treatment of disease.
Disclosure
The symposium and the workshop have been funded by Bröderna Jacob and Marcus Wallenbergs minne.
Kjell Fuxe
Department of Neuroscience, Karolinska Institutet
Stockholm, Sweden
Terrence Kenakin
GlaxoSmithKline Research and Development
Research Triangle Park, NC, USA 27709