G-domain prediction across the diversity of G protein families

Guanine nucleotide binding proteins are characterized by a structurally and mechanistically conserved GTP-binding domain (G domain), indispensable for binding GTP. The G domain comprises five adjacent consensus motifs called G boxes, which are separated by amino acid spacers of different lengths. Several G proteins, discovered over time, are characterized by diverse function and sequence. This sequence diversity is also observed in the G box motifs (specifically the G5 box) as well as the inter-G box spacer length. The Spacers and Mismatch Algorithm (SMA) introduced in this study can predict G-domains in a given protein sequence, based on user-specified constraints for approximate G-box patterns and inter-box gaps in each G protein family. The SMA parameters can be customized as more G proteins are discovered and characterized structurally. Family-specific G box motifs including the less characterized G5 box were predicted with higher accuracy. Overall, our analysis suggests the possible classification of G protein families based on family-specific G box sequences and lengths of inter-G box spacers. SMA can be implemented via a web-based server at https://labs.iitgn.ac.in/datascience/gboxes/

Genetic behavioral screen identifies an orphan anti-opioid system

Opioids target the μ-opioid receptor (MOR) to produce unrivaled pain management, but their addictive properties can lead to severe abuse. We developed a whole-animal behavioral platform for unbiased discovery of genes influencing opioid responsiveness. Using forward genetics in Caenorhabditis elegans, we identified a conserved orphan receptor, GPR139, with anti-opioid activity. GPR139 is coexpressed with MOR in opioid-sensitive brain circuits, binds to MOR, and inhibits signaling to heterotrimeric guanine nucleotide–binding proteins (G proteins). Deletion of GPR139 in mice enhanced opioid-induced inhibition of neuronal firing to modulate morphine-induced analgesia, reward, and withdrawal. Thus, GPR139 could be a useful target for increasing opioid safety. These results also demonstrate the potential of C. elegans as a scalable platform for genetic discovery of G protein–coupled receptor signaling principles.

Neuro Effects of Opioids on the Human Brain

This paper is an examination of the neuro effects of opioids on the human brain. The research examines the brain receptors, region, enzymes, agonists involved, and the results of its interaction with opioids. Examination of the pharmacological effect on receptors located in the neural cell membranes shows that the most important aspect is the modulation of the K and Ca ions channels. This is mediated by the activation of the delta, kappa and mu opioid receptors in the peripheral and central nervous systems. The study found that opioid receptors are coupled by guanine nucleotide binding proteins (G-proteins) to the K+ channel and voltage sensitive Ca++ channel, particularly, the N-type channel. The channels are inhibited if K+ outwards release is increased leading to short polarization time. The outward movement occurs in several regions of the spinal cords, brain, and the myenteric plexus. The rapid K+ outward movement is associated with the observed hyperpolarization and inhibition c4aused by opioids. While the brain has naturally occurring opioids peptides (the b endorphin, the enkephalins and the dynorphin which preferentially interact with the m-receptor, d-receptors and k-receptors respectively), morphine was found to produce exaggerated stimulation of the m-receptor which induce tolerance, addiction, and dependency. The results of opioid interaction with the brain were found to cause depression, nausea, sedation, dysphoria, and impaired cognition, modulation of emotions, stress, rewards, memory and learning.

Allostery and dynamics in small G proteins

The Ras family of small guanine nucleotide-binding proteins behave as molecular switches: they are switched off and inactive when bound to GDP but can be activated by GTP binding in response to signal transduction pathways. Early structural analysis showed that two regions of the protein, which change conformation depending on the nucleotide present, mediate this switch. A large number of X-ray, NMR and simulation studies have shown that this is an over-simplification. The switch regions themselves are highly dynamic and can exist in distinct sub-states in the GTP-bound form that have different affinities for other proteins. Furthermore, regions outside the switches have been found to be sensitive to the nucleotide state of the protein, indicating that allosteric change is more widespread than previously thought. Taken together, the accrued knowledge about small G protein structures, allostery and dynamics will be essential for the design and testing of the next generation of inhibitors, both orthosteric and allosteric, as well as for understanding their mode of action.

Comunicación celular. Transducción de señales acopladas a proteínas G heterotriméricas

<span>Most of the chemical messengers are hydrophilic molecules that exert their biological effect through transmembrane receptors which couple to heterotrimeric guanine nucleotide binding proteins (Gproteins). These G-proteins are signal transductors and they also represent the central part of a molecular machine which is able to receive, integrate and process information carried out by extracellular signals. Several different mechanisms for signal transduction are known. This paper focuses the molecular mechanisms of signal transduction via heterotrimeric G proteins.</span>

Comunicación celular. Transducción de señales acopladas a proteínas G heterotriméricas

<span>Most of the chemical messengers are hydrophilic molecules that exert their biological effect through transmembrane receptors which couple to heterotrimeric guanine nucleotide binding proteins (Gproteins). These G-proteins are signal transductors and they also represent the central part of a molecular machine which is able to receive, integrate and process information carried out by extracellular signals. Several different mechanisms for signal transduction are known. This paper focuses the molecular mechanisms of signal transduction via heterotrimeric G proteins.</span>

The role of Cdc42 and Gic1 in the regulation of septin filament formation and dissociation

Septins are guanine nucleotide-binding proteins that polymerize into filamentous and higher-order structures. Cdc42 and its effector Gic1 are involved in septin recruitment, ring formation and dissociation. The regulatory mechanisms behind these processes are not well understood. Here, we have used electron microscopy and cryo electron tomography to elucidate the structural basis of the Gic1-septin and Gic1-Cdc42-septin interaction. We show that Gic1 acts as a scaffolding protein for septin filaments forming long and flexible filament cables. Cdc42 in its GTP-form binds to Gic1, which ultimately leads to the dissociation of Gic1 from the filament cables. Surprisingly, Cdc42-GDP is not inactive, but in the absence of Gic1 directly interacts with septin filaments resulting in their disassembly. We suggest that this unanticipated dual function of Cdc42 is crucial for the cell cycle. Based on our results we propose a novel regulatory mechanism for septin filament formation and dissociation.

Prostaglandin and the Suppression of Phagocyte Innate Immune Responses in Different Organs

The local and systemic production of prostaglandin E2(PGE2) and its actions in phagocytes lead to immunosuppressive conditions. PGE2is produced at high levels during inflammation, and its suppressive effects are caused by the ligation of the E prostanoid receptors EP2and EP4, which results in the production of cyclic AMP. However, PGE2also exhibits immunostimulatory properties due to binding to EP3, which results in decreased cAMP levels. The various guanine nucleotide-binding proteins (G proteins) that are coupled to the different EP receptors account for the pleiotropic roles of PGE2in different disease states. Here, we discuss the production of PGE2and the actions of this prostanoid in phagocytes from different tissues, the relative contribution of PGE2to the modulation of innate immune responses, and the novel therapeutic opportunities that can be used to control inflammatory responses.