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Lecture 7

BIOL 2P03 Lecture 7: Week 7 Screencast - G-protein Coupled Receptors

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Brock University
Mark K Lukewich

BIOL 2P03 Week 7 Screencast – G-protein Coupled Receptors th th February 27 – March 5 , 2017 Importance of GPCRs • GPCRs represent the largest and most diverse class of plasma membrane receptors – In humans alone, there are approximately 1,000 different GPCRs • Encoded by over 800 genes – Between 1/3 to 1/2 of all pharmaceutical drugs act on GPCRs • GPCRs regulate almost every physiological function in the human body • Dr. Alfred Gilman and Dr. Martin Rodbell were jointly awarded the Nobel Prize in Physiology or Medicine in 1994 for their discovery of GPCRs Signal Detection by GPCRs • GPCRs can detect many different physical and chemical signals, including: – Photons of light – Ions – Lipids – Proteins/peptides – Small organic molecules such as odorants, tastants, neurotransmitters Structure of GPCRs • GPCRs share a common architecture • Extracellular region of receptor helps form ligand binding site and is responsible for modulating ligand access to the binding site • Transmembrane region helps form ligand binding site and undergoes conformational changes necessary to induce intracellular signaling • Intracellular region associates with cytosolic signaling molecules, such as heterotrimeric G-proteins Heterotrimetric G-proteins • Consist of α, β and γ subunits – Exist as a trimer at rest • α subunit and β/γ subunits are bound to the inner leaflet of the plasma membrane • α subunit contains – A binding site for the intracellular region of the GPCR – A binding site for GDP and GTP – A binding site for the β subunit – An intrinsic GTPase • There are several isoforms of each subunit – 16 genes encoding α subunit – 6 genes encoding β subunit – 12 genes encoding γ subunit • Additional variants of each subunit can be created through alternative splicing and post-translational processing • Heterotrimeric G-protein activation occurs through a common pathway for all variants GPCR Signaling Resting State: • The G-protein exists as a heterotrimer with the α, β and γ subunits complexed together • The α subunit is bound to GDP in the resting state GPCR Activation: • When a ligand binds to the GPCR, the GPCR undergoes a conformational change, allowing the heterotrimeric G-protein to bind • The activated receptor acts as a guanine nucleotide exchange factor and stimulates a conformational change in the α subunit that causes the dissociation of GDP • GTP, which is present at much higher concentrations in the cytosol than GDP, then binds to the α subunit, causing it to dissociate from the GPCR and the β/γ subunits G-protein Signaling: • The α subunit (and in some cases the β/γ subunits) can then interact with its effector proteins to initiate intracellular signaling – Effector proteins are membrane-bound Termination of Signal: • The intrinsic GTPase of the α subunit eventually hydrolyzes GTP to GDP (seconds to minutes) • The α subunit can no longer interact with its effector and re-associates with the β/γ subunits Classes of Heterotrimeric G-proteins • Four main classes of heterotrimeric G-proteins have been characterized – Differ based on the amino acid sequences of the α subunits and the effector proteins they regulate • Classified as – Gα s – Gα i – Gα q – Gα 12/13 – Gα seterotrimeric
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