Seminars in Neuroscience最新文献

During the past few years, some roles of GTP-binding proteins in the presynaptic terminal have started to be elucidated. Small GTP-binding proteins, such as rab3a and dynamin, are essential for controlling distinct steps in the cycling of synaptic vesicles, while heterotrimeric G proteins regulate calcium channels, potassium channels, and the secretory machinery either directly or through second messenger pathways. The recent demonstration that G protein-mediated modulation of N-type calcium channels of the presynaptic terminal requires intact syntaxin suggests that G protein regulation of neurotransmitter release may also show an interesting context dependence. Interesting new twists in the G protein story are just emerging.

G-protein-coupled signaling systems play a role in a diversity of normal physiological functions. Logically, one might predict that mutations in genes encoding any one of the G-protein subunits, G-protein-coupled receptors, or effector proteins of a given signaling pathway could lead to disease. Mutations of G-protein-coupled signaling proteins known to cause human diseases are reviewed here, with a primary emphasis on the mammalian phototransduction system.

G protein-coupled receptors are involved in a tremendous range of signaling processes in the nervous system. The outlines of a molecular basis for specificity of receptor–G protein coupling has been established, but important details remain unclear. The second and third intracellular loops of most G protein-coupled receptors and the carboxyl terminus of the G protein α subunit have the most clearly established roles in specificity of coupling. The role of other regions of receptor and G protein, especially the Gβγ subunit, is an area needing more investigation. A discrepancy between specificity observedin vitroand in intact cells suggests a role for targeting and compartmentation of signaling components to account for the striking specificity observed in intact cells. The role of caveolin and PDZ domain-containing proteins will be of significant interest.

X-ray structures for many heterotrimeric G-protein complexes have been solved over the past 5 years. The structures of the G-protein subunits with their bound ligands, in conjugate with each other, and in complex with their regulators and an effector, along with the large quantity of biochemical information, have greatly improved our understanding of how these proteins function in the transduction of signals. In this article, we discuss the characteristics and functions of the heterotrimeric G-proteins in a structural context.

This article highlights recent studies into the roles of the G proteins in two processes required for axon growth: growth cone motility and vesicular transport. Heterotrimeric G proteins are involved in growth cone motility, but their precise roles remain controversial. The small GTP-binding proteins are clearly established regulators of the actin cytoskeleton in fibroblasts, and their functions are just beginning to be explored in the growth cone. Members of the rab subfamily of small GTP-binding proteins have been shown to regulate vesicular transport in every cell type examined thus far, including neurons.

Voltage-dependent Ca²⁺channels are ubiquitous regulators of Ca²⁺-dependent cellular functions. In light of this, it is perhaps not surprising that nature has devised a complex web of G protein-coupled regulatory pathways that appear to tune Ca²⁺channel function appropriately for given physiological demands. We are beginning to identify the molecular components of these pathways and to discover ways of altering them experimentally. Ultimately, it is likely that unique features of each pathway can be exploited to evaluate the physiological roles they play and to determine how they interact with one another as well as with other signaling pathways in cells.

This review describes the emergence of the opioid field, in terms of both endogenous peptides and their receptors. It discusses the basic elements of the opioid system with special attention to the way a large number of endogenous ligands interact with a limited number of opioid receptors. The contribution of the recent cloning of the opioid receptors to our understanding of the system is discussed, including the mechanisms of high affinity and selectivity for endogenous and exogenous ligands, and the mechanisms of signal transduction following acute and sustained exposure to opiates. The expression of opioid receptors and ligands in dopaminoceptive systems relevant to drug reward is described. Finally, the implications of these fundamental observations for new directions in drug abuse research are discussed.

Addiction is a behavioral state characterized by loss of control over drug use and must be appreciated as a chronic relapsing, not acute, disorder. Factors that contribute to the transition from casual use of a drug to loss of control and compulsive use include positive reinforcement (e.g., euphoria, reward), negative reinforcement (e.g., self-medication, alleviation of withdrawal), and conditioned reinforcement (either positive or negative). These same factors may interact to produce relapse even after prolonged periods of abstinence. This review summarizes the current status of animal behavioral and neurobiological models which were designed to address the multiplicity of factors contributing to the addiction process. Use of these models is critical in assessing efficacy of novel treatments, in exploring the neurobiological substrates of reinforcement, dependence, and withdrawal in an effort to identify new targets for treatment intervention, and in uncovering genetic factors that predispose certain individuals to addiction.