Intramembrane receptor–receptor interactions: a novel principle in molecular medicine

Abstract

In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

From the Golgi–Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: Wiring and volume transmission

“…These findings indicate that the electrical component of the mixed synapse may undergo a form of potentiation similar to LTP, which may e.g., be essential for synchronization of oscillations of high frequency (see Nagy et al, 2004). Based on the work on intramembrane receptor-receptor interactions discussed above (see Agnati et al, 2000bAgnati et al, , 2005bFuxe et al, 2003aFuxe et al, , 2007, involving the formation of various types of receptor mosaics containing G-protein-coupled receptors and/or ion channel linked receptors, we now introduce the hypothesis that mixed synapses are formed to enable direct receptor-connexin interactions, which inter alia may help explain the LTP like phenomena observed in the gap junctions (Fig. 11).…”

“…The molecular mechanisms that lead from acute rewarding effects of drugs like cocaine to drug addiction are still unclear. They may involve plastic changes in the receptor networks of the local circuits in the ventral striatum, with alterations in the D2 and D3 containing receptor mosaics (RM) and their receptorreceptor interactions and integrated signaling (RM; highorder heteromers or homomers), leading to changes in the gene expression including adapter proteins contributing to enduring changes in the DA RM, due to their stabilization by the adapter proteins formed (see Fuxe et al, 2007;Marcellino et al, 2007). As to genetic risk factors in DA receptor subtypes and evidence based dopaminergic treatments of substance abuse disorders, see Hurd (2006) and Ivanov et al (2006), respectively.…”

“…All central neurons are therefore under the influence of VT signals, which are continuously integrated with WT signals not only at the cytoplasmatic and nuclear level but also at the plasma membrane level. The mechanism for the integration at the membrane level may mainly be represented by intramembrane receptor-receptor interactions, mainly represented by slow high-affinity G-protein-coupled receptors and synaptic receptors, represented by both fast ion channel linked receptors and slow G-protein-coupled receptors (see Agnati and Fuxe, 2000;Agnati et al, 2003a;Ciruela et al, 2006;Fuxe et al, 2007). Such an integration of WT and VT signals may be the molecular mechanism for the appearance of polymorphic networks (see Agnati and Fuxe, 2000).…”

Fluorescent and Bioluminescent Protein-Fragment Complementation Assays in the Study of G Protein-Coupled Receptor Oligomerization and Signaling

“…The well studied interaction (Fuxe et al, 2007) between the adenosine A 2A and the dopamine D 2 receptors was also recently examined using BiFC (Vidi et al, 2008a). In this case, multicolor BiFC allowed the simultaneous detection of A 2A and D 2 homo-and heteromers in neuronal cells.…”

“…Oligomerization between GPCRs is now recognized to modulate the pharmacological characteristics of the receptors and influence their coupling to G proteins (Fuxe et al, 2007;Milligan, 2007;Pin et al, 2007). The interaction between GPCRs and G proteins is also well documented.…”