G protein-coupled receptors (GPCRs) structure and function

Understanding of how individual cells communicate among them in a complex multicellular organism represents an attractive challenge in all biological sciences. The extracellular intermediates that communicate and carry information between and within cells include hormones, neurotransmitters, small peptides and proteins, ions, and lipids, as well as sensory stimuli such as odorants, pheromones, and light. These intermediates target receptors to induce the adequate cellular response. Receptors have been classified according to their effector mechanisms. This functional classification describes at least three types of cell surface receptors: ion-channel receptors, enzyme-associated receptors, and G protein-coupled receptors (GPCRs). GPCRs share a characteristic topology consisting of seven alpha-helical transmembrane spans, and owe their name to their effector interaction with heterotrimeric G proteins. The utility of this structural template is evident from its wide evolutionary conservation. Members of the largest rhodopsin-like GPCR family can be found in slime mold, yeast, plants, protozoa and the earliest diploblastic metazoa. In vertebrates, this class of surface receptors represents one of the largest families (1-3% of mammalians genome), and up to 1-5% of the total cell proteins. Moreover, GPCRs are the target of >50% of the current therapeutic agents on the market, including a quarter of the 100 top-selling drugs. A better understanding of the mechanisms underlying GPCR signalling may lead to both a better knowledge of cellular communication and the design of new and more effective therapeutic drugs.

Our laboratory is focused on the investigation of the structure and function of GPCRs. In particular, we study the formation of GPCR heterocomplexes. As it becomes clearer that GPCR oligomeric structures are important for activation and have physiological relevance, functional models of GPCR dimers/oligomers are more needed to characterize the structural context of receptor association, and its implication in receptor function. While the existence of GPCR homodimers has been implicated in the molecular mechanisms involved in transmitter recognition and signal transduction, the formation of heterocomplexes raises fundamental questions and combinatorial possibilities that could underlie an higher level of pharmacological diversity, and contribute to cross-talk regulation between transmission systems. We find that serotonin 5-HT_2A receptor (2AR) and metabotropic glutamate 2 receptor (mGluR2) form a receptor complex in mouse and human brain, as well as in vitro in HEK293 cells. We aim to unravel the structural mechanisms underlying the allosteric and functional interactions of the 2AR/mGluR2 complex.

Molecular basis of schizophrenia

Schizophrenia is a brain disease that affects perception, emotion, and cognition. Monoaminergic neurotransmitters have been the principal focus of schizophrenia research for many decades. Several approaches have also linked the neurotransmitter glutamate to the neurochemical alterations in patients with schizophrenia. Notably, clozapine and other atypical antipsychotics have high affinity for serotonin 5-HT_2A receptors (2AR), and metabotropic glutamate receptors 2/3 (mGluR2/3) agonists have recently shown efficacy in treating schizophrenia. We identify a functional brain 2AR/mGluR2 receptor complex that may reconcile the monoaminergic and glutamatergic hypotheses of schizophrenia. We have intriguing results based on in vitro, mouse models and postmortem human brain of schizophrenic subjects suggesting that this novel 2AR/mGluR2 complex may be responsible for some psychotic symptoms in schizophrenia, and that it is the direct target of these two different classes of antipsychotic drugs. Hallucinogenic drugs such as lysergic acid diethylamide (LSD), mescaline or psilocybin induce schizophrenia-like psychoses in humans. We find that the heterotrimeric G proteins and signalling pathways specifically activated by hallucinogens in cortical pyramidal neurons require the 2AR/mGluR2 complex, and that activation of mGluR2 inhibits hallucinogen-specific neuronal signalling pathways. Interestingly, in postmortem human brain of young untreated schizophrenia subjects we find that 2AR is up-regulated and mGluR2 is down-regulated, a pattern that might predispose to psychosis. We hypothesize that the 2AR/mGluR2 complex represents the actual target of both atypical and mGluR2/3 agonist antipsychotics, and our laboratory is focused on the investigation of the 2AR/mGluR2 complex as a potential route to the identification of completely new classes of drugs for schizophrenia.