Synaptic Transmission and Neurotransmitter Pathways

The function of a GPCR in the CNS must be seen in the context of its neuronal cell environment, which is specialized to receive, integrate, and transmit electrical and chemical signals, and its neuroanatomical localization. A wide range of neurotransmitter (NT) molecules that signal through GPCRs have been identified and include amino acids, biogenic amines, peptides, and lipids. NT pathways in the CNS have been mapped according to distribution and connectivity of cells signaling through these molecules and by overall functions and behaviors controlled. Understanding of overall CNS function requires knowledge of how a given protein, e.g., a GPCR, functions within these pathways under normal and pathological conditions.

GPCRs in the CNS are expressed in various types of neurons and in astrocytes and glial cells. The genotype of a GPCR, defined as its protein sequence, is influenced by its specific cell environment to produce the observed receptor phenotype, defined as its pharmacological and signaling properties.2 Cell-specific factors that influence receptor phenotype include differences in receptor reserve, available G protein complement, accessory proteins, lipid environment, and the presence of other GPCRs.

These phenotypic differences may be used to therapeutic advantage to create selective ligands, but also need to be taken into account when characterizing ligands in recombinant systems.

Each individual neuron forms thousands of discrete synapses with other cells, and the resulting networks enable functional effects at individual GPCRs to produce consequences in distant regions of the brain. A typical synapse consists of three basic elements: a presynaptic nerve terminal that releases an NT when the neuron is depolarized, a postsynaptic cell that contains the NT receptor and its effector mechanisms, and a physical distance between the two cells of approximately 200 Angstroms containing specialized extracellular matrix and synaptic machinery proteins, across which the NT diffuses.

GPCRs mediate a relatively slow modulation of neuronal activity, in contrast to the rapid neurotransmissions through ion channels. Postsynaptic GPCR-mediated effector systems include changes in intracellular cAMP levels, increases in phopho-inositol turnover, and indirect modulation of ion channel activity by activation of kinases via release of G-protein p/g subunits. GPCRs also play major roles in presynaptic cells, acting as CNS autoreceptors to decrease release of the same NT or as heteroreceptors, modulating releases of neurotransmitters other than their cognate ligands.

The serotonin 5HT1A receptor is a typical example of an autoreceptor, expressed on cell bodies in the raphe nucleus which, when activated, reduces 5HT release from the terminals of these neurons in the cortex.3-5 There are also more complex negative feedback loops, for example, the activation of postsynaptic metabotropic glutamate receptors (mGluRs) in various CNS regions results in release of endocannabinoid signaling molecules that activate presynaptic cannabinoid CB1 receptors, reducing glutamate release from those neurons.6,7 GPCRs modulate the outflow of CNS circuits in a region- and cell-specific fashion, providing a wealth of options for therapeutic intervention.

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