An essential property of any living cell is its ability to recognize and respond to external stimuli. Cell surface receptors have two major functions: recognition of specific molecules (neurotransmitters, hormones, growth factors, and even sensory signals) and activation of "effectors." Binding of the appropriate agonist (i.e., neurotransmitter or hormone) externally to the receptor alters the conformation (shape) of the protein. Cell surface receptors use a variety of membrane-transducing mechanisms to transform an agonist's message into cellular responses. In neuronal systems, the most typical responses ultimately (in some cases rapidly, in others more slowly) involve changes in transmembrane voltage and hence neuronal changes in excitability. Collectively, the processes are referred to as transmembrane signaling or signal transduction mechanisms. These processes are not restricted to neurons. For example, astrocytes, which were once thought to be unrelated to neurotransmission, have recently been demonstrated to possess voltage-regulated anion channels (VRAC), which not only transport Cl- but also allow efflux of amino acids such as taurine, glutamate, and aspartate (Mulligan and MacVicar 2006).
Interestingly, although increasing numbers of potential neuroactive compounds and receptors continue to be identified, it has become clear that translation of the extracellular signals (into a form that can be interpreted by the complex intracellular enzymatic machinery) is achieved through a relatively small number of cellular mechanisms. Generally speaking, these transmembrane signaling systems, and the receptors that utilize them, can be divided into four major groups (Figure 1-1):
■ Those that are relatively self-contained in structure and whose message takes the form of transmembrane ion fluxes (ionotropic)
■ Those that are multicomponent in nature and generate intracellular second messengers (G protein-coupled)
■ Those that contain intrinsic enzymatic activity (receptor tyrosine kinases and phosphatases)
■ Those that are cytoplasmic and translocate to the nucleus to directly regulate transcription (gene expression) after they are activated by lipophilic molecules (often hormones) that enter the cell (nuclear receptors)
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 NMD A (A/-m ethyl-D-a spa rtate) receptor depolarizes the neuron and brings about an excitatory response, whereas CI" efflux through the T-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 ct, ft, and 7 subunits). The G proteins are attached to the membrane by isoprenoid moieties (fatty acid) via their 7 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 = dopamines receptor; ER = estrogen receptor; GR = glucocorticoid receptor; GRK = G protein-coupled receptor kinase; P = phosphorylation; PR = progesterone receptor.
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