G Protein–Coupled Receptor Signaling

 The GPCR superfamily comprises a large collection of proteins, with approximately 2000 annotated genes in the human genome (∼10% of the entire genome). GPCRs are involved in a large array of physiologic functions, including platelet aggregation and leukocyte chemotaxis. GPCRs are single polypeptides with seven-pass trans membrane domains containing both cytoplasmic and extracellular regions. Ligands for GPCRs are very diverse and include proteins or peptides, amino acids, lipids, and nucleotides that bind at the cell surface where GPCRs are localized. In spite of its vast size and variety of activational ligands, the GPCR superfamily relies upon three main intracellular signaling cascades for communicating receptor activation: the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA), the phosphatidylinositol/phospholipase C, and the Rho GTPase-based cascades.

GPCRs are coupled to a heterotrimeric G protein formed from three unique subunits (α, β, and γ) that are membrane bound. The G-α subunit contains a GTPase domain, which is capable of hydrolyzing GTP to GDP. When bound to GDP, the complex is function ally inactive, with the G-α subunit remaining tightly associated with the other subunits of the GPCR complex. Upon ligand binding to the GPCR, structural conformational changes produce the release of GDP from the heterotrimeric complex, allowing GTP to bind to the G-α subunit. In this GTP-bound form, the G-α subunit dissociates from the G-β and G-γ subunits with which it interacts. The G-α sub unit then proceeds to interact with its downstream cognate targets to affect a particular signal response, depending upon the GPCR and the specific G-α subunit isoform. Among these second-messenger effectors are the cAMP/PKA pathway, ion channels, Rho GTPase, MAPK, PI3K, and inositol-3-phosphate/diacylglycerol (InsP3/DAG) path ways. In the case of the cAMP pathway, adenylate cyclase is down stream of different GPCRs (e.g., adrenergic receptors) and is activated by GTP-bound G-α. Adenylate cyclase converts ATP to cAMP, a freely diffusible second-messenger molecule. A key effector of intra cellular cAMP is PKA, an inactive tetrameric protein complex consisting of two regulatory and two catalytic subunits. Binding of cAMP to the regulatory subunits causes release and activation of the catalytic subunits, which phosphorylate different cellular targets. Among them are the transcription factor cAMP-responsive element (CREB) and several ion channels. In addition to adenylate cyclase, there are other common effectors downstream of GPCRs, such as phospholipase C, a plasma membrane–bound enzyme that cleaves phosphatidyl inositol (PIP2) into two products and messengers: inositol triphosphate (IP3) and DAG. IP3 can diffuse through the cytoplasm and bind receptors in the endoplasmic reticulum (ER), resulting in calcium release to the cytoplasm. Importantly, calcium propagates the signaling cascade through different proteins such as calcineurin and nuclear factor of activated T cells (NFAT) transcription factors (see Fig. 1), which are involved in, for example, IL-2 gene expression. DAG at the plasma membrane binds and activates, in conjunction with calcium, protein kinase C (PKC), which will phosphorylate other downstream targets. Rho guanine nucleotide exchange factor (RhoGEF) is also a target for some G-α subunits. Binding of the G-α subunit to Rho allosterically activates it, causing GTP to be preferentially bound. This, in turn, allows RhoGEFs to activate Rho kinase, which is involved in the cytoskeletal reorganization necessary for changes in cell shape and motility.

Fig1. EXAMPLES OF SIGNALING/TRANSCRIPTIONAL PATH- WAYS PROGRAMMING GENE EXPRESSION. Proteins involved in gene expression are a common target of many signaling pathways, and receptors often stimulate multiple pathways that can regulate common and distinct transcription factors. In the examples shown here, production of PtdIns-3,4,5-P3 by PI3K leads to the activation of the serine/threonine kinase Akt. Akt phosphorylates and inactivates FoxO transcription factors. Ras is activated by the guanine nucleotide exchange factor SOS. Ras activation initiates a cascade of serine/ threonine kinases activity: Ras activates Raf, Raf phosphorylates and activates Mek1, and Mek1 phosphorylates and activates ERK. Phosphorylation of the transcription factor Elk1 by ERK activates gene expression. Increased intra cellular calcium is also a common signaling event. Activation of phospholipase C leads to hydrolysis of PtdIns-4,5-P2 and production of IP3. IP3 binds to its receptor, leading to intracellular calcium release and then extracellular calcium influx. Calcium activates the serine phosphatase calcineurin, which dephosphorylates NFAT proteins, allowing them to enter the nucleus and stimulate transcription. FoxO, Forkhead transcription factors; IP3, inositol triphosphate; NFAT, nuclear factor of activated T cells; PI3K, phosphatidylinositol 3-kinase; SOS, Son of Sevenless.

Chemokine Signaling

 Chemokines mediate cell migration in immune surveillance, inflammation, and development. There are nearly 50 human chemokines divided into four families (CXC, CC, C, and CX3C) on the basis of the pattern of internal cysteine residues; thus C stands for cysteine and X/X3, one or three noncysteine amino acids. Expression of some of these chemokines is induced by inflammatory signals such as TNF-α, interferon-γ, trauma, or microbial infection. There are approximately 20 signaling chemokine receptors, and they are all GPCR receptors; thus the chemokine acts as a ligand, and activation of the chemokine receptor follows the principles described previously. The major downstream effectors are cAMP and calcium messengers. Interestingly, some of the chemokine receptors also bind human immunodeficiency virus (HIV) viral proteins.

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مواضيع ذات صلة

Glucose Metabolism

Cytokine Receptors and Janus-Activated Kinase Signaling

Sterile Mutants, Membrane Receptors and G Factors

Isolation of α2 Protein

Silencing HML and HMR

The Expression and Recombination Paradoxes

Receptor Tyrosine Kinases, Phosphoinosite-3-Kinase, and Mitogen-Activated Protein Kinase Pathways

Mating Type Conversion in Saccharomyces cerevisiae

The Yeast Cell Cycle

Structure and Function of TFIIIA

Switching from Oocyte to Somatic 5S Synthesis

Genome Editing of Immune Effector Cells for Safer and More Potent Cancer Therapies (CAR-T Cells)