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Chapter 9 Intracellular SignalingCopyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.1 Overview of G-protein signaling to protein kinases. Norepinephrine (NE) and acetylcholine (ACh) can stimulate certain receptors that couple through distinct G proteins to different effectors, which results in increased synthesis of second messengers and activation of protein kinases (PKA and PKC). PLC, phospholipase C; PIP2, phosphatidylinositol bisphosphate; DAG, diacylglycerol; CaM, Ca2+- calmodulin dependent; IP3, inositol 1, 4, 5-triphosphate. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.2 GTPase activity of G proteins serves as a timer and amplifier. Receptors activated by neurotransmitters (NT) initiate the GTPase timing mechanism of G proteins by displacement of GDP by GTP. Neurotransmitters thus convert G-GDP (“turned-off state”) to G-GTP (time-limited “turned-on” state). Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.3 Interconversion, catalyzed by excited receptors, of G-protein subunits between inactive and active states. Displacement of GDP with GTP dissociates the inactive heterotrimeric G protein, generating α-GTP and βγ, both of which can interact with their respective effectors and activate them. The system converts into the inactive state after GTP has been hydrolyzed and the subunits have reassociated. From Stryer (1995). Used with permission of W. H. Freeman and Company. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.4 (A) G proteins are held in an inactive state because of very high affinity binding of GDP to their α subunits. When activated by agonist, membrane-bound seven helical receptors (Fig. 9.4 right, glowing magenta) interact with heterotrimeric G proteins (α, amber; β, teal; γ, burgundy) and stimulate dissociation of GDP. This permits GTP to bind to and activate α, which then dissociates from the high-affinity dimer of β and γ subunits. (B) Both activated (GTP-bound) α (lime) and βγ are capable of interacting with downstream effectors. Figure 9.4 shows the interaction of GTP-αs with adenylate cyclase (catalytic domains are mustard and ash). Adenylate cyclase then catalyzes the synthesis of the second messenger cyclic AMP (cAMP) from ATP. (C) Signaling is terminated when α hydrolyzes its bound GTP to GDP. In some signaling systems, GTP hydrolysis is stimulated by GTPase-activating proteins or GAPs (cranberry) that bind to α and stablize the transition state for GTP hydrolysis. (D) Hydrolysis of GTP permits GDP-α to dissociate from its effector and associate again with βγ. The heterotrimeric G protein is then ready for another signaling cycle if an activated receptor is present. This figure is based on the original work of Mark Wall and John Tesmer. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.5 Isoforms of adenylate cyclase (AC). All isoforms are stimulated by αs but differ in the degree of interaction with Ca2+-calmodulin and with βγ derived from inhibitory G proteins. Not shown is the ability of excess βγ to complex with αs and inhibit Group I and Group III adenylate cyclases. Updated from Taussig and Gilman (1995). Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.6 Structures of phosphatidylinositol and phosphatidylcholine. The sites of hydrolytic cleavage by PLC, PLD, and PLA2 are indicated by arrows. FA, fatty acid. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.7 Schematic pathway of IP3 and DAG synthesis and action. Stimulation of receptors coupled to Gq activates PLCβ, which leads to the release of DAG and IP3. DAG activates PKC, whereas IP3 stimulates the IP3 receptor in the endoplasmic reticulum (ER), leading to mobilization of intracellular Ca2+ stores. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.8 Multiple sources of Ca2+ converge on calmodulin and other Ca2+-binding proteins. Cellular levels of Ca2+ can rise either by influx (e.g., through voltage-sensitive channels or ligand-gated channels) or by redistribution from intracellular stores triggered by IP3. Calcium modulates dozens of cellular processes by the action of the Ca2+-calmodulin complex on many enzymes, and calcium has some direct effects on enzymes such as PKC and calpain. CaM kinase, Ca2+-calmodulin-dependent kinase. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.9 Regulation by protein kinases and protein phosphatases. Enzymes and other proteins serve as substrates for protein kinases and phosphoprotein phosphatases, which modify their activity and control them in a dynamic fashion. Multiple signals can be integrated at this level of protein modification. Adapted from Svenningsson et al. (2004). Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.10 Activation of PKA by cAMP. An autoinhibitory segment (blue) of the regulatory subunit (R) dimer interacts with the substrate-binding domain of the catalytic (C) subunits of PKA, blocking access of substrates to their binding site. Binding of four molecules of cAMP reduces the affinity of R for C, resulting in dissociation of constitutively active C subunits. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.11 Domain structure of protein kinases. Protein kinases are encoded by proteins with recognizable structural sequences that encode specialized functional domains. Each of the kinases [PKA, PKG, CaMKII, and PKC] has homologous catalytic domains that are kept inactive by the presence of an autoinhibitory segment (blue lines). Regulatory domains contain sites for binding second messengers such as cAMP, cGMP, Ca2+-calmodulin, DAG, and Ca2+-phosphatidylserine. Alternative splicing creates additional diversity. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.12 Frequency-dependent activation of CaMKII. Autophosphorylation occurs when both neighboring subunits in a holoenzyme are bound to calmodulin. At a high frequency of stimulation (rapid Ca2+ spikes), the interspike interval is too short to allow significant dephosphorylation or dissociation of calmodulin, thereby increasing the probability of autophosphorylation with each successive spike. In a simplified CaMKII with only one ring of six subunits, calmodulinbound subunits are shown in pink and autophosphorylated subunits with trapped calmodulin are shown in red. Adapted from Hudmon and Schulman (2002). Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.13 Domain structure of the catalytic subunits of some Ser/Thr phosphatases. The three major phosphoprotein phosphatases, PP-1, PP-2A, and calcineurin, have homologous catalytic domains but differ in their regulatory properties. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.14 Cross talk between kinases and phosphatases. The state of phosphorylation of protein substrates is regulated dynamically by protein kinases and phosphatases. In the striatum, for example, dopamine stimulates PKA, which converts DARPP-32 into an effective inhibitor of PP-1. This increases the steady-state level of phosphorylation of a hypothetical substrate subject to phosphorylation by a variety of protein kinases. This action can be countered by NMDA receptor stimulation by another stimulus that increases intracellular Ca2+ and activates calcineurin. PP-1 is deinhibited and dephosphorylates the phosphorylated substrate when calcineurin deactives DARPP-32-P. Adapted from Svenningsson et al. (2004). Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.15 Schematic of a generalized RNA polymerase II promoter showing three separate cis-regulatory elements along a stretch of DNA. These elements are two hypothetical activator protein-binding sites and the TATA element. The TATA element is shown binding the TATA-binding protein (TBP). Multiple general transcription factors (IIA, IIB, etc.) and RNA polymerase II (pol II) associate with TBP. Each transcription factor comprises multiple individual proteins complexed together. This basal transcription apparatus recruits RNA polymerase II into the complex and also forms the substrate for interactions with the activator proteins binding to the activator elements shown. Activator 2 is shown to be a substrate for a protein kinase. Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.16 Looping of DNA permits activator (or represser) proteins binding at a distance to interact with the basal transcription apparatus. The basal transcription apparatus is shown as a single box (pol II complex) bound at the TATA element. The activator protein (CREB) is shown as having been phosphorylated. On phosphorylation, many activators, such as CREB, are able to recruit adaptor proteins that mediate between the activator and the basal transcription apparatus. An adaptor protein that binds phosphorylated CREB is called a CREB-binding protein (CBP). Copyright © 2014 Elsevier Inc. All rights reserved.
Copyright © 2014 Elsevier Inc. All rights reserved.FIGURE 9.17 Signal transduction to the nucleus. In this schematic, activation of a neurotransmitter receptor activates cellular signals (G proteins and second-messenger systems). These signals, in turn, regulate the activation of protein kinases, which translocate to the nucleus. Within the nucleus, protein kinases can activate genes regulated by constitutively synthesized transcription factors. A subset of these genes encodes additional transcription factors (third messengers), which can then activate multiple downstream genes. Copyright © 2014 Elsevier Inc. All rights reserved.
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