Principles of cell signaling - UT Southwestern

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39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 614 Perhaps the most diverse family of ligandgated channels is that of the TRP and TRP-like family, of which about 30 have been found in mammals. Distinct forms are found in invertebrates. The TRP channels are Ca2+-selective channels that are formed by tetramers of identical subunits that surround the central channel. Each subunit is composed of a homologous bundle of six membrane-spanning helices, but the N and C termini contain a diverse collection of regulatory and protein interaction domains, including protein kinase domains (whose substrates are currently unknown). All TRP channels allow transmembrane flux of Ca2+ to permit its action as a second messenger, but different TRP isoforms serve numerous physiological functions. The prototypical TRP, found in invertebrate photoreceptors, gates Ca2+ flow from intracellular stores into the cytoplasm to initiate visual signaling. Others admit Ca2+ from outside the cell, and still others allow Ca2+ to enter the endoplasmic reticulum virtually directly from the extracellular space because they form a bridge between the plasma membrane and channels in the endoplasmic reticulum at points where the membranes abut each other. Regulation of TRP channels is perhaps even more diverse. Various TRP channels respond to heat, cold, painful stimuli, pressure, and high or low osmolarity. Many TRPs are regulated either positively or negatively by lipids, such as eicosanoids, diacylglycerol, and PIP 2 . For example, capsaicin, the hot compound in chilis, is an agonist for some vanilloid receptors (TRPVs). Still other TRP channels are mechanosensors that allow cilia to sense fluid flow. The most famous of these is the sensory channel of the hair cell of the inner ear. This channel opens when the apical cilia on the hair cell are bent in response to sound-driven fluid flow. 14.19 Nuclear receptors regulate transcription Key concepts • Nuclear receptors modulate transcription by binding to distinct short sequences in chromosomal DNA known as response elements. • Receptor binding to other receptors, inhibitors, or coactivators leads to complex transcriptional control circuits. • Signaling through nuclear receptors is relatively slow, consistent with their roles in adaptive responses. Nuclear receptors are unique among cellular receptors in that their ligands pass unaided through the plasma membrane. These receptors, when complexed with their ligands, enter the nucleus and regulate gene transcription. Ligands for nuclear receptors include sex steroids (estrogen and testosterone) and other steroid hormones, vitamins A and D, retinoids and other fatty acids, oxysterols, and bile acids. Nuclear receptors are structurally conserved. They consist of a C-terminal ligand binding domain, an N-terminal interaction region that recognizes components of the transcriptional machinery and acts as a transactivation domain, a centrally located zinc finger domain that binds DNA, and, often, another transactivation domain nearer the C-terminus. In the absence of ligand, these receptors are bound to corepressor proteins that suppress their activity. Upon hormone binding, corepressors dissociate and the receptors are assembled in multiprotein complexes with coactivators that modulate receptor action and facilitate transcriptional regulation. As illustrated in FIGURE 14.20, agonists and antagonists bind to distinct receptor conformations (see 14.5 Ligand binding changes receptor conformation). Receptor agonists favor the binding of receptors to coactivators and DNA, and antagonists favor conformations that block coactivator-receptor binding. Nuclear receptors bind with high specificity to hormone response elements in the 5’ untranscribed region of regulated genes. Response elements are typically short direct or inverted repeat sequences, and a gene may contain response elements for several different receptors in addition to binding sites for other transcriptional regulatory proteins. The sex steroid estrogen can bind to two different nuclear receptors, the estrogen receptors ER and ER. Coactivator and corepressor proteins differentially regulate ER and ER in transcriptional complexes that are expressed in specific cell types. Other ligands that bind to these receptors include valuable therapeutic agents. For example, 4 hydroxy-tamoxifen is an estrogen receptor antagonist used in the therapy of estrogen-receptor-positive breast cancer to inhibit growth of residual cancer cells. However, unlike its antagonistic effects on the estrogen receptor in breast, 4 hydroxy-tamoxifen displays weak partial agonist activity in uterus. In the estrogen receptor system, partial agonists are known as selective estrogen receptor modulators (SERMs). Properties that contribute to partial agonist activity include the relative expression of the two estrogen recep- 614 CHAPTER 14 Principles of cell signaling
39057_ch14_cellbio.qxd 8/28/06 5:11 PM Page 615 Estrogen receptor conformation depends on which ligand is bound Agonist-bound conformation Antagonist-bound conformation N N K362 H11 H5 K362 H5 545 C H6 545 542 H3 H11 H6 538 542 H3 538 FIGURE 14.20 The estrogen receptor adopts different conformations when bound to agonists and antagonists. The ligand-binding domain of the estrogen receptor is bound to the agonist estradiol on the left and to the antagonist raloxifene on the right. Note the marked difference in position of helix 12, shown in blue in the active structure and green in the inhibited structure. Reproduced from Brzozowski, A. M., et al. 1997. Molecular basis of agonism and antagonism in the oestrogen receptor. Nature. 389: 753–758. Photo courtesy of M. Brzozowski, University of New York. tors, ER and ER, as well as the expression of repressors and coactivators that interact with each receptor type. Thus, the behavior of nuclear receptor ligands must be considered in the tissue, cellular, and signaling context. 14.20 G protein signaling modules are widely used and highly adaptable Key concepts • The basic module is a receptor, a G protein and an effector protein. • Cells express several varieties of each class of proteins. • Effectors are heterogeneous and initiate diverse cellular functions. Activation of G protein-coupled receptors (GPCRs) and their associated heterotrimeric G proteins is one of the most widespread mechanisms of communicating extracellular signals to the intracellular environment. G protein signaling modules are found in all eukaryotes. Depending on the species, mammals express 500-1000 GPCRs that respond to hormones, neurotransmitters, pheromones, metabolites, local signaling substances, and other regulatory molecules. Essentially all chemical classes are represented among the GPCR ligands. In addition, a roughly equal number of olfactory GPCRs are expressed in olfactory neurons and work in combination to screen compounds in the animal’s environment via the sense of smell. Because GPCRs are involved in many kinds of physiologic responses, they are also one of the most widely used targets for drugs. A minimal G protein signaling module consists of three proteins: a G protein-coupled receptor, the heterotrimeric G protein, and an effector protein, as illustrated in FIGURE 14.21. The receptor activates the G protein on the inner face of the plasma membrane in response to an extracellular ligand. The G protein then activates (or occasionally inhibits) an effector protein that propagates a signal within the cell. Thus, signal conduction in the simplest G protein module is linear. However, as depicted in FIGURE 14.22, a typical animal cell may express a dozen GPCRs, more than six G proteins, and a dozen effectors. Each GPCR regulates one or more G proteins, and each G protein regulates several effectors. Moreover, distinct efficiencies and rates govern each interaction. Thus, a cell’s G protein network is actually a signal-integrating computer whose 14.20 G protein signaling modules are widely used and highly adaptable 615
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Principles of cell signaling - UT Southwestern

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