Journal for Quiz 2

G-protein-coupled receptors (GPCRs) are t he largest family of c ell-surface m olec ules in volved in signa l trans mission. These receptors a re activated by a wide variety of ligands, including peptide an d non-peptide neurotran smitt ers, horm ones, growth factors, odo ra nt molec ules an d light, a nd a re encoded by the largest gene family in most anima l genomes (e.g. 1% of tota l genes in Dr osop h il a a n d >5% of all gene s in Caenorhabditis elegans). Furthermore, >1% of the hum an genome en codes >1000 proteins with a heptahelic al stru ctur e 1 . The large num ber of GPCRs an d the import ance of their physiological roles, which is dir ectly support ed by stu dies perfo rm ed with GPCR knoc kout an imals 2 and t heir link to hereditar y diseases 3 , have made the search fo r n ovel therapeutic drugs an important and constantly expan ding activity in the phar ma ceutical indust ry. Indeed, these receptors ar e the ta rget of >50% of the curr ent th erapeu tic agents on the mar ket, inc luding more than a quar ter of the 100 top-selling drugs with benefits in th e ran ge o f several billio n US dol lars 1 . G-protein-coup led receptors (GPC Rs ) constitute the larges t family of cell- surface molecules involved in s ignal t ransmission. These receptors play key phys iological roles and t heir dysfunction results in sever al diseases . Rec ently, it has been shown t hat many of t he cellular respo nses mediated by GPCR s do not involve the sole stimulat ion of con ventional second-mess enger -generating sys tems, but instead res ult from t he functional integration of an intricate netw ork of intracellular signalin g pathw ays. Effectors for GPCRs that are independent of G proteins ha ve now also been identified, thus c hanging the con ventional view of the GPCR – heterotrimeric-G-protein-associated effector. The emerging infor mat ion is expected to help eluc idate the most basic mechanis m by w hich these receptors exert t heir numerous physiolo gical roles , in addition to determining w hy the perturbation of their function results in many pathological conditions. G-prot ein-coupled receptors and signaling net w orks:emerging paradigms Maria Julia Marinissen and J. Silvio Gutkind 34 Benjafi eld, A.V. an d Morris, B.J . (2000) Association analyses of endothelial nitric oxide syntha se gene polymorphisms in essential hypertension. Am . J. H yper ten s. 13, 994–998 35 Sigusch, H.H. et al. (2000) Lack of associat ion between 27-bp repeat polymorphism in intr on 4 of the endothelial nitr ic oxide synthase gene and t he risk of c oronary art ery disease. Scand. J. Clin. La b. In vest . 60, 229–235 36 Nakagami , H. et al. (1999) Co ronar y art ery disease and endothelial nitr ic oxide synthase an d angiotensin-co nvert ing enzyme gene polymo rphism s. J . Thr omb. Th rom bolysi s 8, 191–195 37 Odawara, M. et al. (1998) Endoth elial nitric oxi de syntha se gene polymorphism an d coronary heart disease in Japa nese NIDDM. Di ab etol ogia 41, 365–366 38 Hibi, K. et al. (1998) Endothelial nitric oxide syntha se gene po lymorphism and acute myoc ardia l infar ction. Hyper ten sion 32, 521–526 39 Ic hihara, S. et al. (1998) Assoc iat ion of a polymorphism of the endothelial co nst itut ive nitr ic oxi de syntha se gene with myocardial infarction in the J apanese population. Am . J. Car di ol. 81, 83–86 40 Burg, M. et al. (1997) Gene-polymorph isms of angiotensin converting enzyme an d endothelial nitric oxide syntha se in patients with prim ary glomerulonephritis. Clin. N ephrol. 48, 205–211 41 Morita, T. et al . (1999) Eff ect of a polymorph ism of endothelial nitric oxi de syntha se gene in Japan ese patients with IgAn ephropathy. Clin. N eph rol. 52, 203–209 42 Y okoyama, K. et al. (1998). High a cc um ulat ion of endothelial nit ric oxide synth ase (ecNOS): a gene polymorphism in patient s with end-stage renal disease. N eph ron 79, 360–361 43 Y okoyama, K. et al. (1999). Relationship between erythr opo ietin administr ation and the endothelial nitr ic oxide synthase gene polymorphism in patient s with hemodialysi s. N eph ron 82, 354–355 44 Y aha shi, Y. et al. (1998) The 27-bp repea t polymorphism in intr on 4 of the endothelial cell nitr ic o xide synthase gene a nd ischemic stroke in a Japan ese population. Bl ood Coag ul . Fibrinolysis 9, 405–409 45 Akar, N. et al. (1999) End othelial n itr ic o xide syntha se intron 4, 27 bp repeat polymorphism in Turkish patients with deep vein thrombosis and cerebrovascular accidents. Thromb. Res. 94, 63–64 46 Yoshimura, M. et al. (2000) Genetic risk factors for coronary ar ter y spasm : signifi cance of endoth elial nitric oxi de syntha se gene T786C and m issense Glu298Asp variants. J . In ves t. Med . 48, 367–374 47 Hingorani, A.D. et al. (1999) Acommon varian t of the endothelial nitr ic oxide synthase (Gl u298Asp) is a m ajor risk factor for coronar y art ery disease in the UK. Circulation 100, 1515–1520 48 Cai, H. et al. (1999) The Glu298Asp (G894T) mut ation at exon 7 of the endothelial nitr ic o xide syntha se gene and coronar y artery disease. J . Mol. Med . 77, 511–514 49 Y oshimura, M. et al. (2000) Genetic risk factors for coronary art ery spasm : signif icance of endothelial nitr ic o xide synthase gene T786C and missense Glu298Asp variant s. J . In vest . Med . 48, 367–374 50 Kato, N. et al. (1999) Lack of evidence for as sociation between the en dothelial nitric oxide synthase gene and hypertension. Hyp ertensi on 33, 933–936 51 Shoj i, M. et al. (2000) Positive association of endothelial nitr ic o xide synthase gene polymorphism with hypert ension in north ern Japan. Li fe S ci. 66, 2557–2562 52 Poirier, O. et al. (1999) Polymorph isms of th e endothelial nitr ic o xide synthase gene – n o consistent association with myoc ardia l infarction in the E CTIM study. Eu r. J . Clin . In vest . 29, 284–290 53 Y oshimura, T. et al. (2000) Association of the missense Glu298Asp variant of the endothelial nitr ic o xide synthase gene with severe preeclampsia. J . S oc. Gyn ecol. In vest . 7, 238–241 54 McNamara, D.M. et al. (1999) The Asp298 varian t of endothelial n itric oxide synthase (eNOS) improves survival in patient s with heart failure. Circulation 100, I507 55 Markus, H.S. et al. (1998) Endothelial nitric oxide syntha se exon 7 polymorphism, ischemic cerebrovascular disease, and carotid ath eroma. Stroke 29, 1908–1911 56 MacLeod, M. J. et al. (1999) No association between Glu/Asp polymorphism of NOS3 gene and ischemic stroke. N eur ology 53, 418–420 57 Akar, N. et al. (2000) No association bet ween Glu/Asp polymorphism of NOS3 gene a nd ischemic stroke. N eur ology 55, 460–461 TRENDSi n Pharmacolog ical Science s Vol.22 No.7 July 2001 http://tip s.trends.com 0165-6147 /01 /$ – see front m atter. Published by Elsevier Science Ltd. PII: S0 165- 614 7(00)0 1678-3 368 Review

Journal for Quiz 2

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