41
3
References
Blumberg PM (1988) Protein kinase C as the receptor for the phorbol ester tumor promoters: sixth Rhoads
memorial award lecture. Cancer Res 48:1–8
Caron MG, Srinivasan Y, Pitha J, Kociolek K, Lefkowitz RJ (1979) Affinity chromatography of the betaadrenergic receptor. J Biol Chem 254:2923–2927
Civelli O (2012) Orphan GPCRs and neuromodulation. Neuron 76:12–21
Conti M, Mika D, Richter W (2014) Cyclic AMP compartments and signaling specificity: role of cyclic nucleotide phosphodiesterases. J Gen Physiol 143:29–38
De Waard M, Hering J, Weiss N, Feltz A (2005) How do G proteins directly control neuronal Ca2+ channel
function? Trends Pharmacol Sci 26:427–436
Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E,
Diehl RE, Mumford RA, Slater EE, Sigal IS, Caron MG, Lefkowitz RJ, Strader CD (1986) Cloning of the gene
and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321:75–79
Fredriksson R, Schioth HB (2005) The repertoire of G-protein-coupled receptors in fully sequenced
genomes. Mol Pharmacol 67:1414–1425
Gurevich VV, Gurevich EV (2015) Arrestins: critical players in trafficking of many GPCRs. Prog Mol Biol
Transl Sci 132:1–14
Hatley ME, Gilman AG, Sunahara RK (2002) Expression, purification, and assay of cytosolic (catalytic)
domains of membrane-bound mammalian adenylyl cyclases. Methods Enzymol 345:127–140
Henderson R, Unwin PN (1975) Three-dimensional model of purple membrane obtained by electron
microscopy. Nature 257:28–32
Ihara K, Umemura T, Katagiri I, Kitajima-Ihara T, Sugiyama Y, Kimura Y, Mukohata Y (1999) Evolution of the
archaeal rhodopsins: evolution rate changes by gene duplication and functional differentiation. J Mol
Biol 285:163–174
Kandel ER, Dudai Y, Mayford MR (2014) The molecular and systems biology of memory. Cell 157:
163–186
Khan SM, Sleno R, Gora S, Zylbergold P, Laverdure JP, Labbe JC, Miller GJ, Hebert TE (2013) The expanding
roles of Gbetagamma subunits in G protein-coupled receptor signaling and drug action. Pharmacol
Rev 65:545–577
Kida S (2012) A functional role for CREB as a positive regulator of memory formation and LTP. Exp Neurobiol
21:136–140
Northup JK, Sternweis PC, Smigel MD, Schleifer LS, Ross EM, Gilman AG (1980) Purification of the regulatory component of adenylate cyclase. Proc Natl Acad Sci U S A 77:6516–6520
Take-Home Messages
5 7 TM receptors represent the largest class of transmembrane proteins in animals and are involved in cellular communication by binding of extracellular
ligands and transducing this information into the cell. They are also called
GPCRs for G-protein-coupled receptors. They function as GEFs for the GDP/GTP
binding site of trimeric G-proteins.
5 Trimeric G-proteins through their Gα-subunits target adenylyl cyclase and
phospholipase C leading to the production of second messengers cAMP or IP3
and DAG. Gα and Gβ/γ-subunits additionally target ion channels and the MAP
kinase pathway.
5 Second messengers activate target enzymes including PKA and PKC. cAMP also
activates ion channels and regulates cross talk with other signalling pathways.
5 Termination of GPCR signalling is mediated by arrestin binding and GTP hydrolysis. After arrestin binding, GPCRs are endocytosed and either sorted back to
the membrane and reused, or degraded. GTP hydrolysis of Gα leads to reassembly of Gα- and Gβ/γ-subunits for new cycles to start.
References
3
References
Blumberg PM (1988) Protein kinase C as the receptor for the phorbol ester tumor promoters: sixth Rhoads
memorial award lecture. Cancer Res 48:1–8
Caron MG, Srinivasan Y, Pitha J, Kociolek K, Lefkowitz RJ (1979) Affinity chromatography of the betaadrenergic receptor. J Biol Chem 254:2923–2927
Civelli O (2012) Orphan GPCRs and neuromodulation. Neuron 76:12–21
Conti M, Mika D, Richter W (2014) Cyclic AMP compartments and signaling specificity: role of cyclic nucleotide phosphodiesterases. J Gen Physiol 143:29–38
De Waard M, Hering J, Weiss N, Feltz A (2005) How do G proteins directly control neuronal Ca2+ channel
function? Trends Pharmacol Sci 26:427–436
Dixon RA, Kobilka BK, Strader DJ, Benovic JL, Dohlman HG, Frielle T, Bolanowski MA, Bennett CD, Rands E,
Diehl RE, Mumford RA, Slater EE, Sigal IS, Caron MG, Lefkowitz RJ, Strader CD (1986) Cloning of the gene
and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin. Nature 321:75–79
Fredriksson R, Schioth HB (2005) The repertoire of G-protein-coupled receptors in fully sequenced
genomes. Mol Pharmacol 67:1414–1425
Gurevich VV, Gurevich EV (2015) Arrestins: critical players in trafficking of many GPCRs. Prog Mol Biol
Transl Sci 132:1–14
Hatley ME, Gilman AG, Sunahara RK (2002) Expression, purification, and assay of cytosolic (catalytic)
domains of membrane-bound mammalian adenylyl cyclases. Methods Enzymol 345:127–140
Henderson R, Unwin PN (1975) Three-dimensional model of purple membrane obtained by electron
microscopy. Nature 257:28–32
Ihara K, Umemura T, Katagiri I, Kitajima-Ihara T, Sugiyama Y, Kimura Y, Mukohata Y (1999) Evolution of the
archaeal rhodopsins: evolution rate changes by gene duplication and functional differentiation. J Mol
Biol 285:163–174
Kandel ER, Dudai Y, Mayford MR (2014) The molecular and systems biology of memory. Cell 157:
163–186
Khan SM, Sleno R, Gora S, Zylbergold P, Laverdure JP, Labbe JC, Miller GJ, Hebert TE (2013) The expanding
roles of Gbetagamma subunits in G protein-coupled receptor signaling and drug action. Pharmacol
Rev 65:545–577
Kida S (2012) A functional role for CREB as a positive regulator of memory formation and LTP. Exp Neurobiol
21:136–140
Northup JK, Sternweis PC, Smigel MD, Schleifer LS, Ross EM, Gilman AG (1980) Purification of the regulatory component of adenylate cyclase. Proc Natl Acad Sci U S A 77:6516–6520
Take-Home Messages
5 7 TM receptors represent the largest class of transmembrane proteins in animals and are involved in cellular communication by binding of extracellular
ligands and transducing this information into the cell. They are also called
GPCRs for G-protein-coupled receptors. They function as GEFs for the GDP/GTP
binding site of trimeric G-proteins.
5 Trimeric G-proteins through their Gα-subunits target adenylyl cyclase and
phospholipase C leading to the production of second messengers cAMP or IP3
and DAG. Gα and Gβ/γ-subunits additionally target ion channels and the MAP
kinase pathway.
5 Second messengers activate target enzymes including PKA and PKC. cAMP also
activates ion channels and regulates cross talk with other signalling pathways.
5 Termination of GPCR signalling is mediated by arrestin binding and GTP hydrolysis. After arrestin binding, GPCRs are endocytosed and either sorted back to
the membrane and reused, or degraded. GTP hydrolysis of Gα leads to reassembly of Gα- and Gβ/γ-subunits for new cycles to start.
References