Note. AC = adenylyl cyclase; Ai, A2 = adenosine receptor subtypes; "1, «i, «2 = adrenergic receptor subtypes; C = cholera toxin; Di, D2 = dopamine receptor subtypes; G«t = olfactory, but also found in limbic areas; G°^ = stimulatory; G«t = transducin; GABAb = "'-aminobutyric acid receptor subtype; 5-HTia, 5-HT2C = serotonin receptor subtypes; Mi, M2, M3, M5 = muscarinic receptor subtypes; ^ = opioid ^ receptor; P = pertussis toxin; PLC = phospholipase C; RGS = regulators of G protein signaling; TxA2 = thromboxane A2 receptor.

aAlthough regulation of Na+/H+ exchange and Ca2+ channels by Gwi-2 and G^i-s has been demonstrated in artificial systems in vitro, these findings await definitive confirmation.

bEffectors are regulated by subunits as a dimer. Autoreceptors and Heteroreceptors

Autoreceptors are receptors located on neurons that produce the endogenous ligand for that particular receptor (e.g., a serotonergic receptor on a serotonergic neuron). By contrast, heteroreceptors are receptor subtypes that are present on neurons that do not contain an endogenous ligand for that particular receptor subtype (e.g., a serotonergic receptor located on a dopaminergic neuron).

Two major classes of autoreceptors play very important roles in fine-tuning neuronal activity. Somatodendritic autoreceptors are present on cell bodies and dendrites and exert critical roles in regulating the firing rate of neurons. In general, activation of somatodendritic autoreceptors (e.g., 02-adrenergic receptors for noradrenergic neurons, serotoninlA [5-HTia] receptors for serotonergic neurons, dopamine2 [D2] receptors for dopaminergic neurons) inhibits the firing rate of the neurons by opening K+ channels and by reducing cyclic adenosine monophosphate (cAMP) levels, both of which may be important in psychiatric disease. For example, TREK-1 is a background K+ channel regulator protein important in 5-HT transmission and potentially in mood-like behavior regulation in mice (Heurteaux et al. 2006). Fundamental mechanisms of neuronal transmission—such as K+ channels, which regulate membrane potentials—may relate to global alterations in brain functioning relevant to psychiatry.

The second major class of autoreceptors, nerve terminal autoreceptors, play an important role in regulating the amount of neurotransmitter released per nerve impulse, generally by closing nerve terminal Ca2+ channels. Both of these types of autoreceptors are typically members of the G protein-coupled receptor family. Neurotransmitter release is known to be triggered by influx and alterations of intracellular calcium, with the functioning of three types of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein [SNAP] receptor) proteins exerting critical roles. Recent advances in our understanding of the distinct kinetics of neurotransmitter release modulators, such as botulinum and tetanus neurotoxins, suggest that these induce prominent alterations in synaptobrevin and syntaxin, leading to calcium-independent mechanisms of neurotransmitter regulation (Sakaba et al. 2005). Most synapses are dependent on influx of Ca2+ through voltage-gated calcium channels for presynaptic neurotransmitter release; in the retina, however, this influx of calcium occurs via glutamatergic AMPA receptors (Chavez et al. 2006). Beyond the receptor level, presynaptic SAD, an intracellular serine threonine kinase, is associated with the active zone cytomatrix that regulates neurotransmitter release (Inoue et al. 2006). These recent data further exemplify the dynamic nature and ongoing advancement of our knowledge pertaining to basic processes involved in neurotransmitter regulation that may possibly aid in advancing treatment of psychopathology.

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