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Cell Signaling (Lecture 2). Types of receptors. Classification of hormones. Lipophillic Hormones with intracellular receptors e.g steroid, thyroxine , retinoic acid
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Classification of hormones • Lipophillic Hormones with intracellular receptors e.g steroid, thyroxine, retinoic acid • Hydrophillic with cell-surface receptors e.g peptide hormones (insulin growth factor and glucagon), small charge molecules (epinephrine and histamine) • Lipophillic with cell surface receptor e.g. prostaglandins
Each Cell Is Programmed to Respond to Specific Combinations of Signaling Molecules • Each cell is exposed to many different signals known as combinatorial signaling. • Each cell type displays a set of receptors that enables it to respond to a corresponding set of signaling molecules. • These signaling molecules work in combinations to regulate the behavior of the cell. Many cells require multiple signals ( green arrows) to survive and additional signals ( red arrows) to proliferate; if deprived of all signals, these cells undergo programmed cell death.
The same signaling molecule can induce different responses in different target cells
General elements of GPCRs • Most abundant class of receptors • Found in organisms from yeast to man • A receptor with 7 membrane-spanning domains • A coupled trimeric G protein • A membrane bound effector protein • Feedback regulation and desensitization of the signalling pathway • A 2nd messenger present in many GPCRs.
Second messengers are molecules that relay signals from receptors on the cell surface to target molecules inside the cell, in the cytoplasm or nucleus. • These components of GPCRs can be mixed and matched to achieve an astonishing number of different pathways • GPCR pathways usually have short term effects in the cells • Allow the cells to respond rapidly to a variety of signals like environmental stimuli (light) or hormonal stimuli (epinephrine)
General features • GPCRs have same orientation in the membrane , 7 transmembrane alpha-helical regions, 4 extra cellular segments, 4 cytosolic segments
The exterior surface of all GPCR consists of hydrophobic amino acids • Amino acids allow the protein to be stably anchored in the hydrophobic core of the plasma membrane • The amino acids are diverse • Which allow different GPCR to bind very different small molecules • These small molecules can be hydrophilic (epinephrine) and hydrophobic (retinol or odorant)
G Protein • Guanine nucleotide-binding proteins, family of proteins involved in transmitting chemical signals originating from outside a cell into the inside of the cell. • G proteins function as molecular switches. Their activity is regulated by their ability to bind to and hydrolyze guanosinetriphosphate (GTP) to guanosinediphosphate (GDP). • When they bind GTP, they are 'on', and, when they bind GDP, they are 'off'. • G proteins belong to the larger group of enzymes called GTPases. Gβ§
Various ligands use G-protein-coupled receptors (GPCRs) to stimulate membrane, cytoplasmic and nuclear targets. GPCRs interact with heterotrimeric G proteins composed of , and subunits that are GDP bound in the resting state. Agonist binding triggers a conformational change in the receptor, which catalyses the dissociation of GDP from the subunit followed by GTP-binding to G and the dissociation of G from G subunits1. The subunits of G proteins are divided into four subfamilies: Gs, Gi, Gq and G12, and a single GPCR can couple to either one or more families of G proteins. Each G protein activates several downstream effectors.
Activation cycle of a G-protein by a G-protein-coupled receptor receiving a ligand
Different G proteins are activated by different GPCRs and inturn regulate different effector proteins. • Effector proteins are in GPCR pathways are either membrane bound ion channels or enzymes that catalyze the formation of the second messengers.
GPCR that regulate ion channels • The simplest cellular responses to a signal is the opening or closing of ion channels essential for transmission of nerve impulses • Nerve impulses are essential to the sensory perception of environmental stimuli (light, odor) to transmission of information to and from the brain and to the stimulation of muscle movement • During transmission of nerve impulses, the rapid opening and closing of ion channels causes changes in the membrane potential • Some neurotransmitter receptors are GPCRs whose effector proteins are Na or K channels
Neurotramsmitter binding to these receptors causes the associated ion channel to open or close leading to changes in the membrane potential e.g acetyl choline involved in K transport