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G-Protein-Coupled Receptors (GPCRs)

Across
GPCR… •C- and N-Teminus along with TM5/6 loop have higher degree of variability- allow GPCRs to distinguish wide variety of ligands
Messenger
GPCR… • membrane bound •Interact with G proteins through a ligand • basic structure • high degree of homology between TM regions therefore also called seven trans membrane (7TM) receptors
•Neurotransmitters •Hormones
•Globular proteins for cell-to-cell communication • Flow of information across plasma membrane • Located mostly in the cell membrane • Receive messages from chemical messengers coming from other cells • Transmit a message into the cell leading to a cellular effect • Different receptors specific for different chemical messengers • Each cell has a range of receptors in the cell membrane making it responsive to different chemical messengers
•Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve • short lived and responsible for messages between individual cells
•Examples: •serotonin •histamine •dopamine • complexity of molecules is no driving force for mediating GPCR function •GPCR must obtain specific confirmation in order to propagate a signal •Compounds that modulate PCR activity must be able to adopt the specific confirmation required by the binding side that they are targeting
•guanine nucleotide-binding proteins • family of proteins that act as molecular switches inside cells •transmit signals from a variety of stimuli from outside a cell to its interior •activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine triphosphate • belong to the larger group of enzymes called GTPases.
•Membrane-bound proteins (3 broad families) •Signal transduction Basic structure: •7 Transmembrane Domains (TMDs), •3 intracellular loops (bind to G protein) • 3 extracellular loops (bind to drug) •N- and C-terminals
Family 2 •15 members • Parathyroid hormone and glucagon receptors.
G-protein dependent… • Machinery → Signal→ Carrier (GPCR)- generates a signal, need a transmitter to send the signal • Secondary messengers- molecules that transmit signals from GPCRs to cellular machinery • Two major types- • cAMP system (cyclic adenosine monophosphate) • Phosphatidylinositol system phosphatidylinositol 4,5-bisphosphate →inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG)
• norepinephrine play a role in memory attention stress reactions energy levels and the regulation of emotions •Clonidine for attention deficit hyperactivity disorder anxiety disorders •Dexmedetomidine is an anxiety reducing, sedative and pain medication
Neurotransmitters: Chemicals released from nerve endings which travel across a nerve synapse to bind with receptors on target cells, such as muscle cells or another nerve. Usually short lived and responsible for messages between individual cells Hormones: Chemicals released from cells or glands and which travel some distance to bind with receptors on target cells throughout the body
Down
Targets GPCR •Agonists • Antagonists •Inverse agonists
Family 5 •24 members •posses an extracellular domain far larger than other classes (structurally largest GPCRs) • Cell adhesion, cellular response • Found in immune cells, CNS and reproductive tissue
• mimic natural ligand, produce same cellular response •binds reversibly to the binding side • similar intermolecular bonds formed as to natural messenger • induced fit alters the shape of the receptor in the same way as the normal messenger
1. GTPase activity of Gα halts production of IP3 and DAG 2. Removal of Ca from cytosol by calcium ATPase pumps 3. DAG converted to glycerol or phosphorylated
Bound to GTP-[on] Bound to GDP-[off]
Family 1 Over 700 members • divided into 19 subfamilies A1 to A19 • serotonin, dopamine, angiotensin II, prostaglandin receptors • function in CNS, cardiovascular regulation and pain receptor
•Find to GPCR but do not elicit a cellular response • binds reversibly to the binding site • intermolecular bonds involved in binding • different induced fit means receptor is not activated • no reaction takes place on antagonist • level of antagonism depends on strength of antagonist binding and concentration • messenger is blocked from the binding site
Phosphatidylinositol Signaling •ligand binds to the GPCR • conformational change in the GPCR • G-protein complex dissociate from GPCR • G alpha Protein released and GTP binds to the G alpha protein •GTP/G-alpha protein complex binds to phospholipase C which hydrolyzes PIP2 • DAG and IP3 released •cytoplasmic IP3 causes the release of cellular calcium stores • membrane bound DAG activates protein kinase C which phosphorylates molecular targets via ATP • protein kinase C activity is augmented by the presence of calcium •system regulated by enzymatic degradation of IP3 and DAG, GTPase activity of the g-alpha protein and removal of cytoplasmic calcium - 100% efficiency relative to natural d