Explore the vast range of titles available.

Two major types of intercellular communication are found in the central nervous system (CNS), namely wiring transmission (point-to-point communication, the prototype being synaptic transmission with axons and terminals) and volume transmission (VT; communication in the extracellular fluid and in the cerebrospinal fluid (CSF)) involving large numbers of cells in the CNS. Volume and synaptic transmission become integrated inter alia through the ability of their chemical signals to activate different types of receptor protomers in heteroreceptor complexes located synaptically or extrasynaptically in the plasma membrane. The demonstration of extracellular dopamine (DA) and serotonin (5-HT) fluorescence around the DA and 5-HT nerve cell bodies with the Falck-Hillarp formaldehyde fluorescence method after treatment with amphetamine and chlorimipramine, respectively, gave the first indications of the existence of VT in the brain, at least at the soma level. There exist different forms of VT. Early studies on VT only involved spread including diffusion and flow of soluble biological signals, especially transmitters and modulators, a communication called extrasynaptic (short distance) and long distance (paraaxonal and paravascular and CSF pathways) VT. Also, the extracellular vesicle type of VT was demonstrated. The exosomes (endosome-derived vesicles) appear to be the major vesicular carriers for VT but the larger microvesicles also participate. Both mainly originate at the soma-dendritic level. They can transfer lipids and proteins, including receptors, Rab GTPases, tetraspanins, cholesterol, sphingolipids and ceramide. Within them there are also subsets of mRNAs and non-coding regulatory microRNAs. At the soma-dendritic membrane, sets of dynamic postsynaptic heteroreceptor complexes (built up of different types of physically interacting receptors and proteins) involving inter alia G protein-coupled receptors including autoreceptors, ion channel receptors and receptor tyrosine kinases are hypothesized to be the molecular basis for learning and memory. At nerve terminals, the presynaptic heteroreceptor complexes are postulated to undergo plastic changes to maintain the pattern of multiple transmitter release reflecting the firing pattern to be learned by the heteroreceptor complexes in the postsynaptic membrane.

Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor–receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural–glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron–glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin–angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease.

GPCRs not only exist as monomers but also as homomers and heteromers in which allosteric receptor-receptor interactions take place modulating the functions of the participating GPCR protomers. GPCRs can also form heteroreceptor complexes with ionotropic receptors and receptor tyrosine kinases modulating their function. Furthermore, adaptor proteins interact with receptor protomers and modulate the interactions. The state of the art is that the allosteric receptor-receptor interactions are reciprocal, highly dynamic and substantially alter the signalling, trafficking, recognition and pharmacology of the participating protomers. The pattern of changes appears to be unique for each heteromer and can favour antagonistic or facilitatory interactions or switch the G protein coupling from e.g., Gi/o to Gq or to beta-arrestin signalling. It gives a new dimension to molecular integration in the nervous system. The future direction should be to determine the receptor interface involving building models of selected heterodimers. This will make it possible to design interface-interfering peptides that specifically disrupt the heterodimer. This will help to determine the functional role of the allosteric receptor-receptor interactions as well as the integration of signals at the plasma membrane by the heteroreceptor complexes versus integration of the intracellular signalling pathways. Integration of signals also at the plasma membrane seems crucial in view of the hypothesis that learning and memory at molecular level takes place by reorganization of homo and heteroreceptor complexes in the postsynaptic membrane. Homo and heteroreceptor complexes are in balance with each other, and their disbalance is linked to diseases. Targeting heteroreceptor complexes represents a novel strategy for treatment of brain disorders.

Many proteins, including G protein–coupled receptors (GPCRs), interact to form oligomers at the cell surface. A combination of bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) in a technique called sequential resonance energy transfer (SRET) extends these methods to study higher-order oligomers of GPCRs or other proteins. Identification of higher-order oligomers in the plasma membrane is essential to decode the properties of molecular networks controlling intercellular communication. We combined bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) in a technique called sequential BRET-FRET (SRET) that permits identification of heteromers formed by three different proteins. In SRET, the oxidation of a Renilla luciferase (Rluc) substrate by an Rluc fusion protein triggers acceptor excitation of a second fusion protein by BRET and subsequent FRET to a third fusion protein. We describe two variations of SRET that use different Rluc substrates with appropriately paired acceptor fluorescent proteins. Using SRET, we identified complexes of cannabinoid CB 1 , dopamine D 2 and adenosine A 2A receptors in living cells. SRET is an invaluable technique to identify heteromeric complexes of more than two neurotransmitter receptors, which will allow us to better understand how signals are integrated at the molecular level.

To elucidate factors underlying the evolution of large brains in cetaceans, we examined 16 brains from 14 cetartiodactyl species, with immunohistochemical techniques, for evidence of non-shivering thermogenesis. We show that, in comparison to the 11 artiodactyl brains studied (from 11 species), the 5 cetacean brains (from 3 species), exhibit an expanded expression of uncoupling protein 1 (UCP1, UCPs being mitochondrial inner membrane proteins that dissipate the proton gradient to generate heat) in cortical neurons, immunolocalization of UCP4 within a substantial proportion of glia throughout the brain, and an increased density of noradrenergic axonal boutons (noradrenaline functioning to control concentrations of and activate UCPs). Thus, cetacean brains studied possess multiple characteristics indicative of intensified thermogenetic functionality that can be related to their current and historical obligatory aquatic niche. These findings necessitate reassessment of our concepts regarding the reasons for large brain evolution and associated functional capacities in cetaceans.

The introduction of allosteric receptor-receptor interactions in G protein-coupled receptor (GPCR) heteroreceptor complexes of the central nervous system (CNS) gave a new dimension to brain integration and neuropsychopharmacology. The molecular basis of learning and memory was proposed to be based on the reorganization of the homo- and heteroreceptor complexes in the postjunctional membrane of synapses. Long-term memory may be created by the transformation of parts of the heteroreceptor complexes into unique transcription factors which can lead to the formation of specific adapter proteins. The observation of the GPCR heterodimer network (GPCR-HetNet) indicated that the allosteric receptor-receptor interactions dramatically increase GPCR diversity and biased recognition and signaling leading to enhanced specificity in signaling. Dysfunction of the GPCR heteroreceptor complexes can lead to brain disease. The findings of serotonin (5-HT) hetero and isoreceptor complexes in the brain over the last decade give new targets for drug development in major depression. Neuromodulation of neuronal networks in depression via 5-HT, galanin peptides and zinc involve a number of GPCR heteroreceptor complexes in the raphe-hippocampal system: GalR1-5-HT1A, GalR1-5-HT1A-GPR39, GalR1-GalR2, and putative GalR1-GalR2-5-HT1A heteroreceptor complexes. The 5-HT1A receptor protomer remains a receptor enhancing antidepressant actions through its participation in hetero- and homoreceptor complexes listed above in balance with each other. In depression, neuromodulation of neuronal networks in the raphe-hippocampal system and the cortical regions via 5-HT and fibroblast growth factor 2 involves either FGFR1-5-HT1A heteroreceptor complexes or the 5-HT isoreceptor complexes such as 5-HT1A-5-HT7 and 5-HT1A-5-HT2A. Neuromodulation of neuronal networks in cocaine use disorder via dopamine (DA) and adenosine signals involve A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complexes in the dorsal and ventral striatum. The excitatory modulation by A2AR agonists of the ventral striato-pallidal GABA anti-reward system via targeting the A2AR-D2R and A2AR-D2R-Sigma1R heteroreceptor complex holds high promise as a new way to treat cocaine use disorders. Neuromodulation of neuronal networks in schizophrenia via DA, adenosine, glutamate, 5-HT and neurotensin peptides and oxytocin, involving A2AR-D2R, D2R-NMDAR, A2AR-D2R-mGluR5, D2R-5-HT2A and D2R-oxytocinR heteroreceptor complexes opens up a new world of D2R protomer targets in the listed heterocomplexes for treatment of positive, negative and cognitive symptoms of schizophrenia.

The discovery of the central monoamine neurons not only demonstrated novel types of brain stem neurons forming global terminal networks all over the brain and the spinal cord,but also to a novel type of communication called volume transmission.It is a major mode of communication in the central nervous system that takes places in the extracellular fluid and the cerebral spinal fluid through diffusion and flow of molecules,like neurotransmitters and extracellular vesicles.The integration of synaptic and volume transmission takes place through allosteric receptor-receptor interactions in heteroreceptor complexes.These heterocomplexes represent major integrator centres in the plasma membrane and their protomers act as moonlighting proteins undergoing dynamic changes and their structure and function.In fact,we propose that the molecular bases of learning and memory can be based on the reorganization of multiples homo and heteroreceptor complexes into novel assembles in the post-junctional membranes of synapses.

The A2A adenosine (A2AR) and D2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A2AR–D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A2AR–D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A2AR–D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on A2AR–D2R receptor–receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A2AR blocked heterodimer interactions and disrupted the allosteric effect of A2AR activation on D2R agonist binding. Protein–protein docking was used to construct a model of the A2AR–D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A2AR–D2R interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A2AR–D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.

Receptor heteromers constitute a new area of research that is reshaping our thinking about biochemistry, cell biology, pharmacology and drug discovery. In this commentary, we recommend clear definitions that should facilitate both information exchange and research on this growing class of transmembrane signal transduction units and their complex properties. We also consider research questions underlying the proposed nomenclature, with recommendations for receptor heteromer identification in native tissues and their use as targets for drug development.

Aim Postmortem brain studies offer enormous opportunities to study molecular mechanisms associated with suicide. In the present study, conventional [35S]GTPγS binding assay and its version‐up method ([35S]GTPγS binding/immunoprecipitation assay) were applied to postmortem human hippocampal membranes prepared from suicide victims and control subjects. Methods By using conventional [35S]GTPγS binding assay, functional activations of Gi/o proteins coupled with multiple GPCRs (5‐HT1A receptor, α2A‐adrenoceptor, M2/M4 mAChRs, adenosine A1 receptor, histamine H3 receptor, group II mGlu, GABAB receptor, μ‐opioid receptor, δ‐opioid receptor, and NOP receptor) were detected by using 15 different agonists. Furthermore, 5‐HT2A receptor‐ and M1 mAChR‐mediated Gαq/11 activation and adenosine A1 receptor‐mediated Gαi‐3 activation were detectable by means of [35S]GTPγS binding/immunoprecipitation assay. Results No significant differences in pharmacological parameters of all concentration‐response curves investigated were found between suicide victims and control subjects. Significant correlations were obtained for the maximal percent increases between some distinct signaling pathways. Conclusion Although only preliminary and auxiliary results were obtained as to the potential differences between suicide victims and control subjects because of the limited number of subjects as well as unmatched age and postmortem delay, adenosine A1 receptor‐mediated Gαi/o activation and 5‐HT2A receptor‐mediated Gαq/11 activation appear worth focusing on in the future investigations. This study also indicates the possibility that some distinct signaling pathways are interrelated with each other, for example, functional activations of Gi/o proteins coupled to M2/M4 mAChR and 5‐HT1A receptor, NOP receptor, and GABAB receptor, and NOP receptor and δ‐opioid receptor. Functional activations of G‐proteins coupled to multiple GPCRs were determined in postmortem human hippocampal membranes. No significant differences were detected between suicide victims and controls.