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Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes

Significance Statement

The discovery of receptor-receptor interactions (RRIs) in the early 1980s together with a more accurate focusing of allosteric mechanisms in proteins, significantly expanded the knowledge on the G protein-coupled receptors (GPCR)-mediated signaling processes in the cells. In particular, increasing evidence was provided that GPCR operate not only as monomers but also as quaternary structures (homodimers, heterodimers and higher-order oligomers), in which networks of electrostatic interactions (hydrogen bonds, van der Waals forces) shape the configuration of the single receptors and the topology of the entire complex, allowing an integration of the incoming signals already at the plasma membrane level through allosteric receptor-receptor interactions. Once established, these integrative mechanisms change the function of the involved GPCR, leading to a sophisticated dynamics of the receptor assembly in terms of modulation of recognition and signaling.

As a consequence, when the interacting receptors are iso-receptors a single neurotransmitter becomes able to induce a spectrum of possible cellular responses that can either work in parallel (redundancy) or interact with each other (complex responses). These factors lead to an astonishing increase in the modes for the recognition/decoding processes that control the cellular biochemical machineries and appear of particular interest for possible therapeutic applications, as indicated by studies on the dopamine iso-receptor complexes D1-D2 and D1-D3 suggesting them as possible targets for neuropsychiatric disorders.

Thus, the expansion of the GPCR field emerging from the characterization of receptor-receptor interactions can also pave the way for the development of novel pharmacological strategies for the treatment of several pathologies, and in the next future this research effort is likely to have a major impact on molecular medicine.

Figure Legend: Micro-domains of the plasma membrane where Receptor-Receptor Interactions (RRIs) can lead to the formation of receptor complexes (Receptor Mosaics, RMs).  From the topology and dynamics of these receptor assemblies a wide spectrum of possible cellular responses to an incoming signal can emerge (Agnati, Guidolin et al., Prog Neurobiol, 2010)

Role of iso-receptors in receptor-receptor interactions with a focus on dopamine iso-receptor complexes.

Journal Reference

Rev Neurosci. 2016 Jan 1;27(1):1-25.

Luigi F. Agnati1 , Diego Guidolin2 , Chiara Cervetto3 , Dasiel O. Borroto-Escuela4 , Kjell Fuxe4 

Show Affiliations
  1. Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Via Campi 287, 41100 Modena, Italy
  2. Department of Molecular Medicine, University of Padova, Via Gabelli 65, 35121 Padova, Italy
  3. Department of Pharmacy, University of Genova, Viale Cembrano 4, 16147 Genova, Italy
  4. Department of Neuroscience, Karolinska Institutet, Retzius vag 8, 17177 Stockholm, Sweden


Intercellular and intracellular communication processes consist of signals and recognition/decoding apparatuses of these signals. In humans, the G protein-coupled receptor (GPCR) family represents the largest family of cell surface receptors. More than 30 years ago, it has been proposed that GPCR could form dimers or higher-order oligomers (receptor mosaics [RMs] at the plasma membrane level and receptor-receptor interactions [RRIs] have been proposed as a new integrative mechanism for chemical signals impinging on cell plasma membranes). The basic phenomena involved in receptor-receptor interactions  are allostery and cooperativity of membrane receptors, and the present paper provides basic information concerning their relevance for the integrative functions of RMs. In this context, the possible role of iso-receptor RM is discussed (with a special focus on dopamine receptor subtypes and on some of the RMs they form with other dopamine iso-receptors), and it is proposed that two types of cooperativity, namely, homotropic and heterotropic cooperativity, could allow distinguishing two types of functionally different RMs. From a general point of view, the presence of iso-receptors and their topological organization within RMs allow the use of a reduced number of signals for the intercellular communication processes, since the target cells can recognize and decode the same signal in different ways. This theoretical aspect is further analyzed here by means of an analogy with artificial information systems. Thus, it is suggested that the ‘multiplexer’ and ‘demultiplexer’ concepts could, at least in part, model the role of RMs formed by iso-receptors in the information handling by the cell.

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