Signaling at the Cell Surface - I

Cell Biology

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Signaling at the Cell Surface
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Signaling Molecules and Cell Surface Receptors
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Kinetics of Cell Signaling
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Intracellular Signal Transduction
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G Protein-Coupled Receptors - I
Ean2e9c6sowbfyihlrpd 180515 s5 khurshid aqsa g protein coupled receptors ii
G Protein-Coupled Receptors - II

Lecture´s Description

Signaling Molecules and Cell Surface Receptors

This Sqadia video is the demonstration of Signaling at the Cell Surface. Communication by extracellular signals usually involves the following steps i.e. synthesis, release of the signaling molecule by the signaling cell, transport of the signal to the target cell. The vast majority of receptors are activated by binding of secreted or membrane-bound molecules. Some receptors, however, are activated by changes in the concentration of a metabolite or by physical stimuli. Signaling Molecules in animals are endocrine, paracrine, and autocrine. Signaling molecules that are integral membrane proteins located on the cell surface also play an important role in development. In receptor specific signaling pathway, external signals induce two major types of cellular responses: changes in the activity or function of specific pre-existing proteins and changes in the amounts of specific proteins produced by a cell.  Signaling from G protein–coupled receptors, often results in changes in the activity of preexisting proteins. The other classes of receptors operate primarily to modulate gene expression. Transcription factors activated in the cytosol by these pathways move into the nucleus, where they stimulate (or occasionally inhibit) transcription of specific target genes. Signaling from receptor tyrosine kinases leads to activation of several cytosolic protein kinases that translocate into the nucleus and regulate the activity of nuclear transcription factors. The response of a cell or tissue to specific external signals is dictated by the particular receptors it possesses, By the signal-transduction pathways they activate, and by the intracellular processes ultimately affected.

Kinetics of Cell Signaling

Maximal cellular response to a signaling molecule may not require activation of all receptors. The insulin receptor, for example, binds insulin and a related hormone called insulin like growth factor 1, but no other peptide hormones. Ligand binding usually can be viewed as a simple reversible reaction, which can be described by the equation. The lower the Kd value, the higher the affinity of a receptor for its ligand. The Kd value is equivalent to the concentration of ligand at which half the receptors contain bound ligand. Like all equilibrium constants, however, the value of Kd does not depend on the absolute values of koff and kon, only on their ratio. For this reason, binding of ligand by two different receptors can have the same Kd values but very different rate constants. About 1 percent of the total receptors will be filled with hormone. Sensitivity of a cell to external signals is determined by the number of surface receptors because the cellular response to a particular signaling molecule depends on the number of receptor-ligand complexes. If RT  1000 (the total number of Epo receptors per cell), Kd 10-10 M, and [RL] 100 (the number of Epo-occupied receptors needed to induce the maximal response), then an Epo concentration of 1.1x 10-11 M will elicit the maximal response. Binding assays are used to detect receptors and determine their kd values. Cell-surface receptors are difficult to identify and purify, mainly because they are present in such minute amounts.  One way to detect weak binding of a ligand to its receptor is in a competition assay with another ligand that binds to the same receptor with high affinity (low Kd value). Synthetic analogs of natural hormones are widely used in research on cell-surface receptors and as drugs i.e. agonists and antagonists. Receptors can be purified by affinity techniques or expressed from cloned genes.

Intracellular Signal Transduction

Second messengers carry signals from many receptors. The binding of ligands (“first messengers”) to many cell surface receptors leads to a short-lived increase (or decrease) in the concentration of certain low-molecular-weight intracellular signaling molecules termed second messengers. GTPase Switch Proteins, the guanine nucleotide–binding proteins are turned “on” when bound to GTP and turned “off” when bound to GDP. Signal-induced conversion of the inactive to active state is mediated by a guanine nucleotide–exchange factor (GEF), which causes release of GDP from the switch protein. There are two classes of GTPase switch proteins: trimeric (large) G proteins and monomeric (small) G proteins such as Ras and various Ras-like proteins. Activation of all cell surface receptors leads directly or indirectly to changes in protein phosphorylation through the activation of protein kinases or protein phosphatases. In some signaling pathways, the receptor itself possesses intrinsic kinase or phosphatase activity; in other pathways, the receptor interacts with cytosolic or membrane associated kinases. Clustering of neurotransmitter receptors in the region of the postsynaptic plasma membrane adjacent to the presynaptic cell promotes rapid and efficient signal transmission. Proteins containing PDZ domains play a fundamental role in organizing the plasma membrane of the postsynaptic cell. Certain lipids in the plasma membrane, particularly cholesterol and sphingolipids, are organized into aggregates, called lipid rafts, that also contain specific proteins. In mammalian cells, lipid rafts termed caveolae are of particular interest.

G Protein-Coupled Receptors - I

All G protein–coupled receptors (GPCRs) contain seven membrane-spanning regions with their N-terminal segment on the exoplasmic face and their C-terminal segment on the cytosolic face of the plasma membrane. Stimulation of a coupled receptor causes activation of the G protein, which in turn modulates the activity of an associated effector protein. The variations on the theme of GPCR signaling arise because multiple G proteins are encoded in eukaryotic genomes. The G and G subunits of trimeric G proteins are tethered to the membrane by covalently attached lipid molecules. Epinephrine is particularly important in mediating the body’s response to stress. In mammals, the liberation of glucose and fatty acids can be triggered by binding of epinephrine to -adrenergic receptors on the surface of hepatic and adipose cells. Although all epinephrine receptors are G protein– coupled receptors, the different types are coupled to different G proteins. The 1-adrenergic receptor is coupled to a Gi protein that inhibits adenylyl cyclase. Some bacterial toxins contain a subunit that penetrates the plasma membrane of cells and catalyzes a chemical modification of Gsα·GTP that prevents hydrolysis of bound GTP to GDP. X-ray crystallographic analysis has pinpointed the regions in Gs·GTP that interact with adenylyl cyclase. This enzyme is a multipass transmembrane protein with two large cytosolic segments containing the catalytic domains. Positive and negative regulation of adenylyl cyclase activity occurs in some cell types, providing fine-tuned control of the cAMP level.

G Protein-Coupled Receptors - II

In multicellular animals virtually all the diverse effects of cAMP are mediated through protein kinase A (PKA), also called cAMP-dependent protein kinase. Inactive PKA is a tetramer consisting of two regulatory (R) subunits and two catalytic (C) subunits. In adipose cells, epinephrine-induced activation of PKA promotes phosphorylation and activation of the phospholipase that catalyzes hydrolysis of stored triglycerides to yield free fatty acids and glycerol. Although PKA acts on different substrates in different types of cells, it always phosphorylates a serine or threonine residue that occurs within the same sequence motif. The first cAMP-mediated cellular response to be discovered was the release of glucose from glycogen that occurs in muscle and liver cells stimulated by epinephrine or other hormones whose receptors are coupled to Gs protein. The epinephrine-stimulated increase in cAMP and subsequent activation of PKA enhance the conversion of glycogen to glucose 1-phosphate in two ways: by inhibiting glycogen synthesis and by stimulating glycogen degradation. PKA phosphorylates and thus inactivates glycogen synthase, the enzyme that synthesizes glycogen. Signal amplification is possible because both receptors and G proteins can diffuse rapidly in the plasma membrane. A single receptor hormone complex causes conversion of up to 100 inactive Gs molecules to the active form. Several factors contribute to termination of the response to hormones recognized by -adrenergic receptors and other receptors coupled to Gs. regulatory mechanisms for signaling include feedback suppression, heterologous desensitization, and homologous desensitization. Anchoring proteins localize effects of camp to specific subcellular regions. These proteins, referred to as A kinase–associated proteins (AKAPs), have a two-domain structure with one domain conferring a specific subcellular location and another that binds to the regulatory subunit of protein kinase A.

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