Biochemie 4. Cell communication - GPCR

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1 Biochemie 4 Cell communication - GPCR 1

2 Lecture outline General principles - local and long-distance signaling - classes of receptors - molecular switches and second messengers Receptor tyrosine kinases (RTKs) - receptors and receptor activation - Downstream signaling - Variation of the scheme : Cytokine and TGFβ receptors G protein-coupled receptors (GPCRs) - receptors - Downstream signaling 2

3 RTK dimerization induces trans-phosphorylation 3

4 Important examples of signal cascades 4

5 Ras-GTP activates the MAP kinase cascade The MAP kinase module includes three protein kinases Raf: Ser/Thr kinase MEK: dual specificity (Tyr and Ser/Thr) kinase MAPK (ERK): Ser/Thr kinase (enters the nucleus to modulate gene expression) 5

6 The IP 3 /DAG/PKC pathway 6

7 Activation of PKB Unphosphorylated Bad protein promotes cell death 7

8 Downregulation of RTK signaling Phosphatases dephosphorylate RTKs, all factors along the MAPK cascade, and their final targets GAPs stimulate GTP hydrolysis of Ras, accelerate off-switching of Ras-GTP Endocytosis 8

9 Ligand binding induces dimerization Ligand either causes dimerization of cytokine receptors or induces conformational change of already dimerized receptors to bring the JAKs in close proximity. 9

10 Pathways activated by cytokine receptors 10

11 STAT function SH2 domain of STAT (Signal Transduction and Activation of Transcription) proteins allows interaction with phosphorylated receptor At receptor, STAT proteins are phosphorylated by JAK kinases Phospho-STAT dissociates from receptor and dimerizes Dimerization exposes NLS in STAT proteins and allows nuclear import In nucleus, STAT proteins bind to specific enhancer sequences. 11

12 Summary / Concepts Receptor Kinase Kinase specificity Receptor tryosine kinases Intrinsic Tyrosine Tyrosine-kinaseassociated receptors (Cytokine receptors) Kinase associated (Jak) Tyrosine TGFβ receptors Intrinsic Serine/Threonine 12

13 Lecture outline General principles - local and long-distance signaling - classes of receptors - molecular switches and second messengers Receptor tyrosine kinases (RTKs) - receptors and receptor activation - Downstream signaling - Variation of the scheme : Cytokine and TGFβ receptors G protein-coupled receptors (GPCRs) - receptors - Downstream signaling 13

14 G-protein coupled receptor signaling 14

15 G protein-coupled receptors (GPCRs) Seven-pass transmembrane proteins structurally similar to bacteriorhodopsin Largest group of receptors (>700 in humans) Highly conserved from yeast to human About 50% of known drugs are working through GPCRs Signal transduced through a membrane-bound trimeric G-protein Activated by diverse signals (hormones, neutrotransmitters, light, odor)

16 Structure of G protein-coupled receptors 7 transmembrane helices N- and C- terminal segments: variable size, few to >100 residues ligand binding: N-terminal extracellular domain Retinal OR: central pocket among the extracellular ends of helices 16

17 GPCR undergo conformational changes

18 GTPase switch proteins Two classes of GTPases: a) heterotrimeric G proteins (G a ) b) small, monomeric GTPases (e.g. Ras) GEF: guanine nucleotide exchange factor GAP: GTPase activating protein ligand-bound GPCRs are GEFs for heterotrimeric G proteins! 18

19 Stimulation of GPCRs Signal molecule induces conformational change of the receptor Receptor with bind α subunit of the heterotrimeric G-protein which induces the dissociation of the bound GDP (GPCR is GEF for G-protein) once GTP binds to the α subunit the heterotrimeric complex dissociates into α and/or βγ subunits (in most cases) (or undergoes conformational changes without the dissociation) α and/or βγ subunits of G-protein bind to target protein α subunit will finally hydrolyze GTP to GDP + P and deactivate itself plus βγ complex 19

20 Ligand-induced effector activation by GPCRs 20

21 Classes of G proteins 27 G a, 5 G b, 13 G g for 1000 receptors membrane anchors: G a : myristoylation, palmitoylation; G g : prenylation all effector proteins are membrane-bound ion channels or enzymes that catalyze formation of second messengers 21

22 Effectors of GPCRs GPCRs Heterotrimeric G-proteins Adenylyl cyclase Phospholipase C Ion channels (all membrane bound protein) 22

23 Regulation of adenylyl cyclase 23

24 Regulation of adenylyl cyclase Adenylyl cyclase (also called adenylate cyclase) is a transmembrane protein with 12 membrane spanning helices; the catalytic important protein domains reside in the cytoplasm. Adenylyl cyclase produces cyclic AMP (camp) camp in turn activates PKA (camp-dependent protein kinase) PKA catalyzes cellular reactions (e.g. involved in glycogen breakdown) or activates transcriptional regulators 24

25 Structure and function of adenylyl cyclase 25

26 Positive and negative control of adenylyl cyclase by GPCRs Example: adipose cells 26

27 Multiple responses are mediated by Gs and camp Several diseases identified in humans that have mutations in G alpha subunits. The patients suffer from metabolic abnormalities, abnormal bone development or mental retardation. E.g. McCune Albright syndrome (prevents downregulation of camp signaling through mutation of Gs): hyperpigmentation and abnormal bone growth 27

28 Cholera toxin Cholera: Vibrio cholerae massive diarrhea, fluid loss 6 L/hour A1 cholera toxin: hexameric complex AB 5 complex; After endocytosis, the A1 chain is released by reduction of disulfid bonds and activated by binding to the human Arf6 protein. A1 catalyzes the ADP-ribosylation of Arg residue of G sa and thereby impairs GTP hydrolysis (no hydrolysis any more). A2 B 5 28

29 Cholera toxin ADP-ribosylation of Arg residue of G sa impairs GTP hydrolysis constitutively active G sa -GTP camp levels increase constitutive activation of intestinal Na + pumps secretion of large volumes water and Cl- into the gut 29

30 Pertussis toxin Whooping cough (Keuchhusten): Bordatella pertussis infant deaths per year ADP-ribosylation of Cys residue of G ia impairs nucleotide exchange constitutively inactive G ia -GDP camp levels increase secretion of fluids and mucus in epthelial cells of respiratory tract 30

31 Protein Kinase A is a major mediator of cellular responses to camp Protein Kinase A (PKA) alias camp-dependent protein kinase inactive tetramer of regulatory and catalytic subunits (R 2 C 2 ) Regulatory subunits bind A-kinase anchoring proteins (AKAPs) to specifically localize PKA in cells. basal cellular camp levels too low to bind R cooperative binding of camp to R signaling specificity depends on cell-specific PKA isoform and substrate(s) 31

32 Examples for GCPR camp signaling Different types of cellular responses activated: a) changes in the activity of specific pre-existing proteins (occurs rapidly after pathway activation) => Glycogen metabolism b) changes gene transcription (usually by activation of transcription factors or changing their localization) => CRE-binding proteins 32

33 Examples for GCPR camp signaling 33

34 Example II: Transcriptional regulation e.g. liver cells: camp induces expression of enzymes involved in converting C 3 -compounds to glucose target genes possess campresponse element (CRE) CRE-binding protein (CREB) binds to CRE upon phosphorylation of Ser-133 by PKA CREB-binding to CRE recruits other transcriptional co-activator to the basal transcription machinery, resulting in transcription of target gene 34

35 Odorant receptors regulate camp-gated ion channels Nobel Prize in Physiology or Medicine for 2004 to Richard Axel and Linda Buck Recognition of up to 10,000 different odours by 1,000 odorant GPCRs (about 3% of our genome) Odorant binding activates receptor, leading to active G olfa -GTP, activation of adenylyl cyclase, and rise in camp levels camp binding opens camp-gated ion channels, leading to membrane depolarization and Ca 2+ influx Ca 2+ opens Ca 2+ -gated Cl - channels, depolarization opens voltage-gated Na + - channels, triggering an action potential 35

36 Regulation of phospholipase C 36

37 Regulation of Phospholipase C Activates the IP 3 /DAG/PKC pathway (Inositol phospholipid pathway) Initiated by the activation of phospholipase C: GPCRs: signaling via Phospholipase Cb; (serves as GAP for Gαq) RTKs: signaling via Phospholipase Cg (contains SH2 domain) Phospholipase C cleaves inositol phospholipid (PI 4,5-bisphosphate, PIP2) present in the inner layer of the membrane to produce inositol 1,4,5- trisphosphate (IP3) and diacylglyerol (DAG) IP3 (second messenger): activates Ca 2+ channels in the ER DAG (second messenger): activates protein kinase C (PKC) together with Ca 2+ 37

38 The IP 3 /DAG/PKC pathway 38

39 Ca 2+ signal Ca 2+ is an important intracellular signal (second messenger) which signals egg to divide, muscles to contract etc. Normally, Ca 2+ concentrations are low in the cytoplasm but high in the ER (endoplasmic reticulum) and the extracellular space. Activates (together with DAG) PKC and other Ca 2+ -responsive proteins (e.g. Calmodulin) 39

40 Calmodulin Calmodulin is a Ca 2+ responsive protein. Calmodulin changes its conformation upon binding of four Ca 2+ ions and wraps around target proteins. Ca 2+ /calmodulin-dependent protein kinases (CaM kinase) are activated by calmodulin and in turn starts to phosphorylate other proteins. 40

41 Calmodulin/CaM kinase Molecular memory 41

42 Example: Activation of Tubby by PLCb Tubby: putative transcription factor linked to obesity activity regulated by cellular localization inactive Tubby is tightly bound to plasma membrane PIP 2 hormone-binding to G q -coupled receptors (Serotonin; others?) activates PLCb, leading to PIP 2 hydrolysis and re-localization of Tubby to the nucleus where it activates transcription of as yet unknown target genes Tub mutant or knockout mice: obesity 42

43 Regulation of ion channels 43

44 Regulation of ion channels Rhodopsin-transducin signaling cascade: Rhodopsin receptor (GPCR) activates transducin (G protein) α subunit of transducin activates cgmp phosphodiesterase resulting in reduced levels of cgmp and closing of cation channels in the membrane. GPCRs as ion channels regulators in heart muscle cells: Acetylcholine binds to GPCRs (muscarinic ACh receptor) of heart muscle membrane Activated βγ complex facilitates K+ ligand channels to open (membrane is hyperpolarized) 44

45 Light receptors - cgmp-gated ion channels Rod photoreceptors ( Stäbchen ) 45

46 Activation of rhodopsin activated opsin is unstable and dissociates into opsin and free all-trans-retinal sensitivity: single photon -> 1mV signal 5 photons -> detectable by humans 46

47 cgmp phosphodiesterase is the effector of light absorption dark: open ion channels, low membrane potential, depolarization, constant neurotransmitter release from synaptic body light: closed of ion channels, hyperpolarization, decrease in neurotransmitter release brain: "light 47

48 GPCRs as ion channels regulator in the heart in cardiac muscle: ACh binding to muscarinic ACh receptor leads to reduction in rate of heart muscle contraction effector: G bg -gated K + - channel, opening results in hyperpolarization of membrane 48

49 Silencing of GPCR signaling 49

50 Silencing of GPCR signaling Ligand binding: - short-lived active state (rhodopsin) - reduced affinity for ligand upon nucleotide exchange to G a -GTP (b-adrenergic receptor) RGS proteins: GAPs for G a -GTP, stimulate GTP hydrolysis, accelerate switching off of G a 25 members with distinct specificities Turnover of second messenger: e.g. camp phosphodiesterase 50

51 Desensitization Desensitization: Attenuation of signaling in the presence of continuing agonist stimulation. Gonzales Iglesias et al., 2000

52 Desensitization by receptor phosphorylation Phosphorylation of Ser and Thr residues at the cytosolic face of GPCRs reduces affinity for heterotrimeric G proteins. Feedback suppression: Activated downstream kinases PKA and PKC phosphorylate receptor (independent of ligand binding!) -> uncoupling from G protein -> reduced activation by ligand binding 52

53 Desensitization by GRKs/arrestins Homologous desensitization : Phosphorylation of additional cytosolic residues by G-protein coupled receptor kinases (GRKs), e.g. rhodopsin kinase, BARK GRKs phosphorylate only activated/ligand-bound receptor GRKs are recruited to the plasma membrane by binding to G bg or by lipid anchors. GRKs are allosterically activated by activated receptors. Hyperphosphorylation by GRKs promotes binding of arrestins, which (a) sterically block interactions with G proteins (b) facilitates endocytosis (serve as adaptor protein to couple the receptor to the endocytosis machinery) 53

54 Summary / Concepts GPCRs are 7 transmembrane proteins which activate a class of trimeric G- proteins (the GPCR act as GEF for the G-proteins). Activation of the receptor (by light or a extracellular signal molecule) causes conformational changes of the GPCR leading to the binding and activation of the heterotrimeric G-protein. The trimeric G-proteins act as molecular switches that transmit the signal onward. Two subunits of the trimeric G-proteins have membrane anchors and therefore all effector molecules of these G-proteins have to be at the plasma membrane. 54

55 Summary / Concepts Some heterotrimeric G-proteins directly activate (or inactivate) the enzyme adenylyl cyclase thereby altering the intracellular concentration of the second messenger camp. Other G-proteins directly activate phospholipase C, which generates the second messengers inositol trisphosphate (IP3) and diacylglycerol. Still, other G-proteins directly regulate ion channels in the plasma membrane. camp levels are regulated by adenylyl cyclase and camp phosphodiesterase. PKA, PKC and CaM-kinases are activated through GPCR and phosphorlyate selected target proteins thereby altering protein activity. Desensitization is the attenuation of signaling in the presence of continuing agonist stimulation. 55

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