The mysterious trace amines: protean neuromodulators of synaptic transmission in mammalian brain.

The trace amines are a structurally related group of amines and their isomers synthesized in mammalian brain and peripheral nervous tissues. They are closely associated metabolically with the dopamine, noradrenaline and serotonin neurotransmitter systems in mammalian brain. Like dopamine, noradrenaline and serotonin the trace amines have been implicated in a vast array of human disorders of affect and cognition. The trace amines are unique as they are present in trace concentrations, exhibit high rates of metabolism and are distributed heterogeneously in mammalian brain. While some are synthesized in their parent amine neurotransmitter systems, there is also evidence to suggest other trace amines may comprise their own independent neurotransmitter systems. A substantial body of evidence suggests that the trace amines may play very significant roles in the coordination of biogenic amine-based synaptic physiology. At high concentrations, they have well-characterized presynaptic "amphetamine-like" effects on catecholamine and indolamine release, reuptake and biosynthesis; at lower concentrations, they possess postsynaptic modulatory effects that potentiate the activity of other neurotransmitters, particularly dopamine and serotonin. The trace amines also possess electrophysiological effects that are in opposition to these neurotransmitters, indicating to some researchers the existence of receptors specific for the trace amines. While binding sites or receptors for a few of the trace amines have been advanced, the absence of cloned receptor protein has impeded significant development of their detailed mechanistic roles in the coordination of catecholamine and indolamine synaptic physiology. The recent discovery and characterization of a family of mammalian G protein-coupled receptors responsive to trace amines such as beta-phenylethylamine, tyramine, and octopamine, including socially ingested psychotropic drugs such as amphetamine, 3,4-methylenedioxymethamphetamine, N,N-dimethyltryptamine, and lysergic acid diethylamide, have revitalized the field of scientific studies investigating trace amine synaptic physiology, and its association with major human disorders of affect and cognition.

Properties of the Group IV phospholipase A2 family.

The Group IV phospholipase A2 family is comprised of six intracellular enzymes commonly called cytosolic phospholipase A2 (cPLA2) alpha, cPLA2beta, cPLA2gamma, cPLA2delta, cPLA2epsilon and cPLA2zeta. They are most homologous to phospholipase A and phospholipase B/lysophospholipases of filamentous fungi particularly in regions containing conserved residues involved in catalysis. However, a number of other serine acylhydrolases (patatin, Group VI PLA2s, Pseudomonas aeruginosa ExoU and NTE) contain the Ser/Asp catalytic dyad characteristic of Group IV PLA2s, and recent structural analysis of patatin has confirmed its structural similarity to cPLA2alpha. A characteristic of all these serine acylhydrolases is their ability to carry out multiple reactions to varying degrees (PLA2, PLA1, lysophospholipase and transacylase activities). cPLA2alpha, the most extensively studied Group IV PLA2, is widely expressed in mammalian cells and mediates the production of functionally diverse lipid products in response to extracellular stimuli. It has PLA2 and lysophospholipase activities and is the only PLA2 that has specificity for phospholipid substrates containing arachidonic acid. Because of its role in initiating agonist-induced release of arachidonic acid for the production of eicosanoids, cPLA2alpha activation is important in regulating normal and pathological processes in a variety of tissues. Current information available about the biochemical properties and tissue distribution of other Group IV PLA2s suggests they may have distinct mechanisms of regulation and functional roles.

Psychostimulants, madness, memory... and RGS proteins?

The ingestion of psychostimulant drugs by humans imparts a profound sense of alertness and well-being. However, repeated use of these drugs in some individuals will induce a physiological state of dependence, characterized by compulsive behavior directed toward the acquisition and ingestion of the drug, at the expense of customary social obligations. Drugs of abuse and many other types of experiences share the ability to alter the morphology and density of neuronal dendrites and spines. Dopaminergic modulation of corticostriatal synaptic plasticity is necessary for these morphological changes. Changes in the density of dendritic spines on striatal neurons may underlie the development of this pathological pattern of drug-seeking behavior. Identifying proteins that regulate dopaminergic signaling are of value. A family of proteins, the regulators of G protein signaling (RGS) proteins, which regulate signaling from G protein-coupled receptors, such as dopamine and glutamate, may be important in this regard. By regulating corticostriatal synaptic plasticity, RGS proteins can influence presynaptic activity, neurotransmitter release, and postsynaptic depolarization and thereby play a key role in the development of this plasticity. Pharmacological agents that modify RGS activity in humans could be efficacious in ameliorating the dependence on psychostimulant drugs.

In through the out door: nuclear localization of the regulators of G protein signaling.

The regulators of G protein signaling (RGS) are an extraordinary class of diverse multifunctional signaling proteins best known for their potent capacity to down-regulate the activity of Galpha subunits at the plasma membrane. In certain circumstances, some RGS proteins undergo translocation to the nucleus or plasma membrane from the cytoplasm. Translocation demonstrates a potentially dynamic alternative mechanism for Galpha subunit or effector regulation. The nuclear localization of the regulators of G protein signaling proteins further suggests these proteins possess even greater functional heterogeneity than that envisioned previously, as regulators of transcription and cell cycle control.

The yeast G protein alpha subunit Gpa1 transmits a signal through an RNA binding effector protein Scp160.

In yeast Saccharomyces cerevisiae the G protein betagamma subunits (Ste4/Ste18) have long been known to transmit the signal required for mating. Here we demonstrate that GTPase-deficient mutants of Galpha (Gpa1) directly activate the mating response pathway. We also show that signaling by activated Gpa1 requires direct coupling to an RNA binding protein Scp160. These findings suggest an additional role for Gpa1 and reveal Scp160 as a component of the mating response pathway in yeast.

Regulation of stress response signaling by the N-terminal dishevelled/EGL-10/pleckstrin domain of Sst2, a regulator of G protein signaling in Saccharomyces cerevisiae.

All members of the regulator of G protein signaling (RGS) family contain a conserved core domain that can accelerate G protein GTPase activity. The RGS in yeast, Sst2, can inhibit a G protein signal leading to mating. In addition, some RGS proteins contain an N-terminal domain of unknown function. Here we use complementary whole genome analysis methods to investigate the function of the N-terminal Sst2 domain. To identify a signaling pathway regulated by N-Sst2, we performed genome-wide transcription profiling of cells expressing this fragment alone and found differences in 53 transcripts. Of these, 40 are induced by N-Sst2, and nearly all contain a stress response element (STRE) in the promoter region. To identify components of a signaling pathway leading from N-Sst2 to STREs, we performed a genome-wide two-hybrid analysis using N-Sst2 as bait and found 17 interacting proteins. To identify the functionally relevant interacting proteins, we analyzed all of the available gene deletion mutants and found three (vps36 Delta, pep12 Delta, and tlg2 Delta) that induce STRE and also repress pheromone-dependent transcription. We selected VPS36 for further characterization. A vps36 Delta mutation diminishes signaling by pheromone as well as by downstream components including the G protein, effector kinase (Ste11), and transcription factor (Ste12). Conversely, overexpression of Vps36 enhances the pheromone response in sst2 Delta cells but not in wild type. These findings indicate that Vps36 and Sst2 have opposite and opposing effects on the pheromone and stress response pathways, with Vps36 acting downstream of the G protein and independently of Sst2 RGS activity.