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FIGURE 1–1. Major receptor subtypes in the central nervous system.This figure depicts the four major classes of receptors in the CNS. (A) Ionotropic receptors. These receptors comprise multiple protein subunits that are combined in such a way as to create a central membrane pore through this complex, allowing the flow of ions. This type of receptor has a very rapid response time (milliseconds). The consequences of receptor stimulation (i.e., excitatory or inhibitory) depend on the types of ions that the receptor specifically allows to enter the cell. Thus, for example, Na+ entry through the NMDA (N-methyl-d-aspartate) receptor depolarizes the neuron and brings about an excitatory response, whereas Cl efflux through the -aminobutyric acid type A (GABAA) receptor hyperpolarizes the neuron and brings about an inhibitory response. Illustrated here is the NMDA receptor regulating a channel permeable to Ca2+, Na+, and K+ ions. The NMDA receptors also have binding sites for glycine, Zn2+, phencyclidine (PCP), MK801/ketamine, and Mg2+; these molecules are able to regulate the function of this receptor. (B) G protein–coupled receptors (GPCRs). The majority of neurotransmitters, hormones, and even sensory signals mediate their effects via seven transmembrane domain–spanning receptors that are G protein–coupled. The amino terminus of the G protein is on the outside of the cell and plays an important role in the recognition of specific ligands; the third intracellular loop and carboxy terminus of the receptor play an important role in coupling to G proteins and are sites of regulation of receptor function (e.g., by phosphorylation). All G proteins are heterotrimers (consisting of , , and subunits). The G proteins are attached to the membrane by isoprenoid moieties (fatty acid) via their subunits. Compared with the ionotropic receptors, GPCRs mediate a slower response (on the order of seconds). Detailed depiction of the activation of G protein–coupled receptors is given in Figure 1–2. Here we depict a receptor coupled to the G protein Gs (the s stands for stimulatory to the enzyme adenylyl cyclase [AC]). Activation of such a receptor produces activation of AC and increases in cAMP levels. G protein–coupled pathways exhibit major amplification properties, and, for example, in model systems researchers have demonstrated a 10,000-fold amplification of the original signal. The effects of cAMP are mediated largely by activation of protein kinase A (PKA). One major downstream target of PKA is CREB (cAMP response element–binding protein), which may be important to the mechanism of action of antidepressants. (C) Receptor tyrosine kinases. These receptors are activated by neurotrophic factors and are able to bring about acute changes in synaptic function, as well as long-term effects on neuronal growth and survival. These receptors contain intrinsic tyrosine kinase activity. Binding of the ligand triggers receptor dimerization and transphosphorylation of tyrosine residues in its cytoplasmic domain, which then recruits cytoplasmic signaling and scaffolding proteins. The recruitment of effector molecules generally occurs via interaction of proteins with modular binding domains SH2 and SH3 (named after homology to the src oncogenes–src homology domains); SH2 domains are a stretch of about 100 amino acids that allows high-affinity interactions with certain phosphotyrosine motifs. The ability of multiple effectors to interact with phosphotyrosines is undoubtedly one of the keys to the pleiotropic effects that neurotrophins can exert. Shown here is a tyrosine kinase receptor type B (TrkB), which upon activation produces effects on the Raf, MEK (mitogen-activated protein kinase/ERK), extracellular response kinase (ERK), and ribosomal S6 kinase (RSK) signaling pathway. Some major downstream effects of RSK are CREB and stimulation of factors that bind to the AP-1 site (c-Fos and c-Jun). (D) Nuclear receptors. These receptors are transcription factors that regulate the expression of target genes in response to steroid hormones and other ligands. Many hormones (including glucocorticoids, gonadal steroids, and thyroid hormones) are able to rapidly penetrate into the lipid bilayer membrane, because of their lipophilic composition, and thereby directly interact with these cytoplasmic receptors inside the cell. Upon activation by a hormone, the nuclear receptor–ligand complex translocates to the nucleus, where it binds to specific DNA sequences, referred to as hormone responsive elements (HREs), and regulates gene transcription. Nuclear receptors often interact with a variety of coregulators that promote transcriptional activation when recruited (coactivators) and those that attenuate promoter activity (corepressors). However, nongenomic effects of neuroactive steroids have also been documented, with the majority of evidence suggesting modulation of ionotropic receptors. This figure illustrates both the genomic and the nongenomic effects. ATF1 = activation transcription factor 1; BDNF = brain-derived neurotrophic factor; CaMKII = Ca2+/calmodulin–dependent protein kinase II; CREM = cyclic adenosine 5'-monophosphate response element modulator; D1 = dopamine1 receptor; D5 = dopamine5 receptor; ER = estrogen receptor; GR = glucocorticoid receptor; GRK = G protein–coupled receptor kinase; P = phosphorylation; PR = progesterone receptor.

FIGURE 1–2. G protein–coupled receptors and G protein activation.All G proteins are heterotrimers consisting of , , and subunits. The receptor shuttles between a low-affinity form that is not coupled to a G protein and a high-affinity form that is coupled to a G protein. (A) At rest, G proteins are largely in their inactive state, namely, as heterotrimers, which have GDP (guanosine diphosphate) bound to the subunit. (B) When a receptor is activated by a neurotransmitter, it undergoes a conformational (shape) change, forming a transient state referred to as a high-affinity ternary complex, comprising the agonist, receptor in a high-affinity state, and G protein. A consequence of the receptor interaction with the G protein is that the GDP comes off the G protein subunit, leaving a very transient empty guanine nucleotide binding domain. (C) Guanine nucleotides (generally GTP) quickly bind to this nucleotide binding domain; thus, one of the major consequences of active receptor–G protein interaction is to facilitate guanine nucleotide exchange—this is basically the "on switch" for the G protein cycle. (D) A family of GTPase-activating proteins for G protein–coupled receptors has been identified, and they are called regulators of G protein signaling (RGS) proteins. Since activating GTPase activity facilitates the "turn off" reaction, these RGS proteins are involved in dampening the signal. Binding of GTP to the subunit of G proteins results in subunit dissociation, whereby the -GTP dissociates from the subunits. Although not covalently bound, the and subunits remain tightly associated and generally function as dimers. The -GTP and subunits are now able to activate multiple diverse effectors, thereby propagating the signal. While they are in their active states, the G protein subunits can activate multiple effector molecules in a "hit and run" manner; this results in major signal amplification (i.e., one active G protein subunit can activate multiple effector molecules; see Figure 1–11). The activated G protein subunits also dissociate from the receptor, converting the receptor to a low-affinity conformation and facilitating the dissociation of the agonist from the receptor. The agonist can now activate another receptor, and this also results in signal amplification. Together, these processes have been estimated to produce a 10,000-fold amplification of the signal in certain models. (E) Interestingly, the subunit has intrinsic GTPase activity, which cleaves the third phosphate group from GTP (G-P-P-P) to GDP (G-P-P). Since -GDP is an inactive state, the GTPase activity serves as a built-in timing mechanism, and this is the "turn off" reaction. (F) The reassociation of -GDP with is thermodynamically favored, and the reformation of the inactive heterotrimer () completes the G protein cycle.
Table Reference Number
TABLE 1–1. Key features of G protein subunits

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