Abstract
Nitric oxide (NO) is a small molecule produced by nitric oxide synthase (NOS) with various physio-pathological functions in the body. There are three main NOS isoforms, including the endothelial (eNOS), inducible (iNOS), and neuronal NOS (nNOS), that exist in the peripheral organs and nervous systems of humans and rodents. Moreover, NOS includes other identified NOS isoforms, such as retinal Muller glial cells (mNOS), mitochondrial (mtNOS), penile (PnNOS), testis-specific (TnNOS), and invertebrate Drosophila NOS (dNOS), which are the lesser-known types. It is proposed that the versatile functions of NOS isoforms depend on various NOS splice variant subtypes and their expression in the neural (e.g., brain, and spinal cord) and non-neuronal tissues (e.g., lung, kidney, liver, and GI tract). Therefore, this review summarizes the NOS subtypes, splice variants, targeted splicing expression in the body, and their proposed physio-pathological functions. At last, alternative NOS subtypes and isoforms, which have previously received scant attention, will be addressed in this article.
Keywords: Nitric oxide synthase, endothelial NOS, neuronal NOS, inducible NOS, isoform subtype, nitric oxide.
Graphical Abstract
[http://dx.doi.org/10.1523/JNEUROSCI.0294-06.2006] [PMID: 17151270]
[http://dx.doi.org/10.1074/jbc.272.17.11392] [PMID: 9111048]
[http://dx.doi.org/10.1042/bj3570593] [PMID: 11463332]
[http://dx.doi.org/10.1126/science.1090100] [PMID: 14684825]
[http://dx.doi.org/10.1016/S0166-2236(96)10074-6] [PMID: 9061868]
[http://dx.doi.org/10.1016/S0016-5085(00)70171-5] [PMID: 10784584]
[http://dx.doi.org/10.1073/pnas.92.20.9072] [PMID: 7568075]
[PMID: 10390607]
[http://dx.doi.org/10.1021/cr000661e] [PMID: 11942792]
[http://dx.doi.org/10.1016/j.febslet.2013.10.032] [PMID: 24211446]
[PMID: 19079538]
[PMID: 1383325]
[http://dx.doi.org/10.1111/j.1476-5381.1990.tb12977.x] [PMID: 2110019]
[http://dx.doi.org/10.1016/j.tem.2019.10.001] [PMID: 31690508]
[http://dx.doi.org/10.1016/j.ccr.2011.10.011] [PMID: 22523434]
[http://dx.doi.org/10.1016/0896-6273(94)90348-4] [PMID: 7520252]
[http://dx.doi.org/10.1038/375068a0] [PMID: 7536899]
[http://dx.doi.org/10.1089/ars.2008.2234] [PMID: 18715148]
[http://dx.doi.org/10.1523/JNEUROSCI.16-09-02881.1996] [PMID: 8622119]
[http://dx.doi.org/10.1523/JNEUROSCI.19-07-02489.1999] [PMID: 10087063]
[http://dx.doi.org/10.3390/ijms221910340] [PMID: 34638682]
[http://dx.doi.org/10.1159/000201214] [PMID: 7895925]
[http://dx.doi.org/10.3923/pjbs.2014.1185.1189] [PMID: 26027164]
[http://dx.doi.org/10.1556/036.102.2015.4.2] [PMID: 26690027]
[http://dx.doi.org/10.1002/jemt.1165] [PMID: 11747089]
[http://dx.doi.org/10.1111/j.1476-5381.2011.01500.x] [PMID: 21615722]
[http://dx.doi.org/10.1146/annurev.pa.36.040196.000503] [PMID: 8725383]
[http://dx.doi.org/10.1111/j.1749-6632.2002.tb04068.x] [PMID: 12076975]
[http://dx.doi.org/10.1016/0306-4522(93)90271-G] [PMID: 8101643]
[PMID: 8897874]
[http://dx.doi.org/10.1016/S0306-4522(97)00308-4] [PMID: 9466466]
[http://dx.doi.org/10.1073/pnas.97.26.14602] [PMID: 11121062]
[http://dx.doi.org/10.1038/sj.cr.7290267] [PMID: 15686630]
[http://dx.doi.org/10.1515/BC.2004.001] [PMID: 14977040]
[http://dx.doi.org/10.1155/2013/948765]
[http://dx.doi.org/10.1038/nrg2164] [PMID: 17726481]
[http://dx.doi.org/10.1016/j.gene.2004.10.022] [PMID: 15656968]
[http://dx.doi.org/10.1016/j.jmb.2011.04.041] [PMID: 21530537]
[http://dx.doi.org/10.1161/CIRCRESAHA.108.183426] [PMID: 18948630]
[http://dx.doi.org/10.3892/br.2014.407] [PMID: 25798239]
[http://dx.doi.org/10.1152/physrev.2001.81.1.209] [PMID: 11152758]
[http://dx.doi.org/10.1007/0-306-46816-6_3]
[http://dx.doi.org/10.1242/jcs.01187] [PMID: 15169833]
[http://dx.doi.org/10.1016/S0304-3940(97)00601-0] [PMID: 9310303]
[http://dx.doi.org/10.1515/revneuro-2019-0111] [PMID: 32739909]
[http://dx.doi.org/10.1016/0006-8993(96)00675-0] [PMID: 8883910]
[http://dx.doi.org/10.1016/S0092-8674(00)81053-3] [PMID: 8625413]
[http://dx.doi.org/10.1016/0092-8674(95)90471-9] [PMID: 7545544]
[http://dx.doi.org/10.1073/pnas.95.13.7625] [PMID: 9636200]
[http://dx.doi.org/10.1074/jbc.271.43.27184] [PMID: 8900212]
[http://dx.doi.org/10.1111/j.1471-4159.2007.04528.x] [PMID: 17419805]
[http://dx.doi.org/10.1016/0304-3940(93)90898-U] [PMID: 7512249]
[http://dx.doi.org/10.1046/j.1471-4159.1995.65031342.x] [PMID: 7543934]
[http://dx.doi.org/10.1002/(SICI)1097-4547(19970515)48:4<372:AID-JNR9>3.0.CO;2-8] [PMID: 9169863]
[http://dx.doi.org/10.1016/j.neuint.2013.06.002] [PMID: 23770205]
[http://dx.doi.org/10.1007/s00702-013-1066-1] [PMID: 23851625]
[http://dx.doi.org/10.1002/med.21599] [PMID: 31192483]
[http://dx.doi.org/10.1046/j.1365-201X.2003.01182.x] [PMID: 14510775]
[http://dx.doi.org/10.1371/journal.pone.0021618] [PMID: 21738735]
[http://dx.doi.org/10.1046/j.1471-4159.1995.64051965.x] [PMID: 7722484]
[http://dx.doi.org/10.1002/ana.410440717]
[http://dx.doi.org/10.1523/JNEUROSCI.19-09-03440.1999] [PMID: 10212304]
[http://dx.doi.org/10.1084/jem.177.6.1779] [PMID: 7684434]
[http://dx.doi.org/10.1093/nar/24.9.1682] [PMID: 8649986]
[http://dx.doi.org/10.1007/s10059-009-0010-6] [PMID: 10102579]
[http://dx.doi.org/10.2174/1570159X18666200429001549] [PMID: 32348225]
[http://dx.doi.org/10.1073/pnas.95.26.15769] [PMID: 9861045]
[http://dx.doi.org/10.1002/glia.10145] [PMID: 12379909]
[http://dx.doi.org/10.1042/BST0370886]
[http://dx.doi.org/10.1016/S0016-5085(96)70055-0] [PMID: 8831582]
[http://dx.doi.org/10.1073/pnas.90.23.11419] [PMID: 7504305]
[http://dx.doi.org/10.1161/STROKEAHA.106.478826] [PMID: 17446423]
[http://dx.doi.org/10.1016/S0306-4522(02)00082-9] [PMID: 12044445]
[http://dx.doi.org/10.1016/S0006-8993(99)01444-4] [PMID: 10407101]
[http://dx.doi.org/10.1016/S0306-4522(03)00210-0] [PMID: 12809689]
[http://dx.doi.org/10.1073/pnas.0500485102] [PMID: 15781872]
[http://dx.doi.org/10.1073/pnas.0810968106] [PMID: 19139419]
[http://dx.doi.org/10.1016/S0021-9258(17)37441-0] [PMID: 7509810]
[http://dx.doi.org/10.1038/sj.leu.2403169] [PMID: 14574328]
[http://dx.doi.org/10.1073/pnas.90.8.3491] [PMID: 7682706]
[http://dx.doi.org/10.1016/0092-8674(84)90496-3] [PMID: 6205765]
[http://dx.doi.org/10.1073/pnas.92.25.11514] [PMID: 8524794]
[http://dx.doi.org/10.1021/bi00036a003] [PMID: 7547858]
[http://dx.doi.org/10.1002/j.1460-2075.1995.tb00038.x] [PMID: 7543842]
[http://dx.doi.org/10.1073/pnas.93.10.4891] [PMID: 8643499]
[http://dx.doi.org/10.1182/blood.V92.3.1031] [PMID: 9680373]
[http://dx.doi.org/10.1021/bi00003a013] [PMID: 7530045]
[http://dx.doi.org/10.1126/science.1373522] [PMID: 1373522]
[http://dx.doi.org/10.1074/jbc.270.18.10625] [PMID: 7537735]
[http://dx.doi.org/10.1093/acprof:oso/9780195306637.001.0001]
[http://dx.doi.org/10.1097/00004647-199701000-00012] [PMID: 8978391]
[http://dx.doi.org/10.1016/S1089-8603(02)00127-1] [PMID: 12223183]
[http://dx.doi.org/10.1007/s11886-019-1165-1] [PMID: 31227915]
[http://dx.doi.org/10.1152/jappl.1997.82.1.359] [PMID: 9029239]
[http://dx.doi.org/10.1152/ajpcell.1998.275.1.C260] [PMID: 9688857]
[http://dx.doi.org/10.1113/jphysiol.2008.164947] [PMID: 19047200]
[http://dx.doi.org/10.1515/BC.2008.152] [PMID: 18713021]
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.112.197301] [PMID: 23108656]
[http://dx.doi.org/10.1096/fj.06-7434com] [PMID: 17264164]
[http://dx.doi.org/10.1016/j.biochi.2010.03.020] [PMID: 20363286]
[http://dx.doi.org/10.4314/ahs.v21i3.25] [PMID: 35222579]
[http://dx.doi.org/10.1006/bbrc.1994.1146] [PMID: 7509596]
[http://dx.doi.org/10.2217/14622416.8.12.1723]
[http://dx.doi.org/10.1093/cvr/cvt267] [PMID: 24302629]
[http://dx.doi.org/10.1006/niox.2000.0300] [PMID: 11020335]
[http://dx.doi.org/10.1074/jbc.273.35.22267] [PMID: 9712842]
[http://dx.doi.org/10.1074/jbc.M710178200] [PMID: 18316370]
[http://dx.doi.org/10.1097/00008571-200003000-00005] [PMID: 10762001]
[http://dx.doi.org/10.1074/jbc.M801933200] [PMID: 18390539]
[http://dx.doi.org/10.1161/01.ATV.0000016248.51577.1F] [PMID: 12006409]
[http://dx.doi.org/10.1073/pnas.0503853102] [PMID: 16284254]
[http://dx.doi.org/10.1172/JCI119673] [PMID: 9294118]
[http://dx.doi.org/10.1155/2021/9945277]
[http://dx.doi.org/10.1177/002215540004800808] [PMID: 10898804]
[http://dx.doi.org/10.1515/BC.2002.154] [PMID: 12437128]
[http://dx.doi.org/10.1016/j.molbrainres.2005.04.008] [PMID: 15913838]
[http://dx.doi.org/10.1007/s00418-005-0123-8] [PMID: 16341869]
[http://dx.doi.org/10.3390/ijms22189990] [PMID: 34576155]
[http://dx.doi.org/10.3390/biomedicines9121905] [PMID: 34944725]
[http://dx.doi.org/10.1016/j.neulet.2004.12.032] [PMID: 15823420]
[http://dx.doi.org/10.1161/01.ATV.19.11.2584] [PMID: 10558999]
[http://dx.doi.org/10.1186/ar2465] [PMID: 19007429]
[http://dx.doi.org/10.1159/000491393] [PMID: 29929191]
[http://dx.doi.org/10.1007/s00125-013-3084-9] [PMID: 24186360]
[http://dx.doi.org/10.1177/17590914211035020] [PMID: 34596459]
[http://dx.doi.org/10.1007/s12551-011-0060-9] [PMID: 28510048]
[http://dx.doi.org/10.1007/s12975-020-00831-y] [PMID: 32661768]
[http://dx.doi.org/10.1161/01.ATV.17.11.2479] [PMID: 9409218]
[http://dx.doi.org/10.3389/fphys.2016.00206] [PMID: 27313545]
[http://dx.doi.org/10.1111/j.1471-4159.2006.04407.x] [PMID: 17250678]
[http://dx.doi.org/10.1074/jbc.272.45.28187] [PMID: 9353265]
[http://dx.doi.org/10.1111/j.1471-4159.2010.06813.x] [PMID: 20492351]
[http://dx.doi.org/10.1073/pnas.0407294102] [PMID: 15937123]
[http://dx.doi.org/10.1097/00005072-199712000-00003] [PMID: 9413277]
[http://dx.doi.org/10.1006/bbrc.1998.8404] [PMID: 9535811]
[http://dx.doi.org/10.1172/JCI810] [PMID: 9502774]
[http://dx.doi.org/10.1161/01.RES.0000259042.04576.6a] [PMID: 17272813]
[http://dx.doi.org/10.1016/S0021-9258(20)30099-5] [PMID: 7528745]
[http://dx.doi.org/10.1007/BF00539015] [PMID: 8597645]
[http://dx.doi.org/10.1007/BF00350898] [PMID: 7536496]
[http://dx.doi.org/10.1074/jbc.274.25.17559] [PMID: 10364190]
[http://dx.doi.org/10.1006/bbrc.1993.1726] [PMID: 7686743]
[http://dx.doi.org/10.1016/j.brainres.2009.06.041] [PMID: 19545548]
[http://dx.doi.org/10.1073/pnas.92.4.1242] [PMID: 7532307]
[http://dx.doi.org/10.1615/CritRevNeurobiol.v13.i1.20] [PMID: 10223522]
[http://dx.doi.org/10.1074/jbc.M209988200] [PMID: 12403769]
[http://dx.doi.org/10.1016/S0169-328X(00)00220-5] [PMID: 11146102]
[http://dx.doi.org/10.1681/ASN.2015050515] [PMID: 26647426]
[http://dx.doi.org/10.1093/ndt/gfn676] [PMID: 19073653]
[http://dx.doi.org/10.1152/ajpgi.00226.2001] [PMID: 11804857]
[http://dx.doi.org/10.1159/000111211] [PMID: 9208206]
[http://dx.doi.org/10.1523/JNEUROSCI.21-11-j0002.2001] [PMID: 11344254]
[http://dx.doi.org/10.1073/pnas.94.7.3396] [PMID: 9096405]
[http://dx.doi.org/10.1124/mol.54.2.305] [PMID: 9687572]
[http://dx.doi.org/10.1152/ajpgi.00279.2009] [PMID: 19679819]
[http://dx.doi.org/10.1371/journal.pone.0200834] [PMID: 30028847]
[http://dx.doi.org/10.1152/ajpgi.00152.2018] [PMID: 30285465]
[http://dx.doi.org/10.3389/fmed.2014.00017] [PMID: 25705628]
[http://dx.doi.org/10.1161/01.ATV.0000223143.88128.19] [PMID: 16627802]
[http://dx.doi.org/10.1042/bj3550357] [PMID: 11284722]
[http://dx.doi.org/10.1124/jpet.102.035055] [PMID: 12538799]
[http://dx.doi.org/10.1016/j.molbrainres.2003.12.015] [PMID: 15046863]
[http://dx.doi.org/10.1016/S0959-4388(97)80064-5] [PMID: 9232802]
[http://dx.doi.org/10.1002/jnr.22133] [PMID: 19479987]
[http://dx.doi.org/10.1074/jbc.271.19.11204] [PMID: 8626668]
[PMID: 10851306]
[http://dx.doi.org/10.1172/JCI40736] [PMID: 20124730]
[http://dx.doi.org/10.1046/j.1471-4159.2003.01626.x] [PMID: 12614337]
[http://dx.doi.org/10.1016/0092-8674(93)90615-W] [PMID: 7505721]
[http://dx.doi.org/10.1016/S0002-9440(10)64380-5] [PMID: 11786430]
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.02.033] [PMID: 19358992]
[http://dx.doi.org/10.1073/pnas.93.13.6770] [PMID: 8692893]
[http://dx.doi.org/10.1124/mol.54.2.258] [PMID: 9687566]
[http://dx.doi.org/10.1006/bbrc.1996.1324] [PMID: 8806605]
[http://dx.doi.org/10.1016/j.metabol.2007.06.003] [PMID: 17884453]
[http://dx.doi.org/10.1371/journal.pone.0003387] [PMID: 18852886]
[http://dx.doi.org/10.1007/s00424-019-02268-1] [PMID: 30900045]
[http://dx.doi.org/10.1016/S0021-9258(17)31854-9] [PMID: 7520440]
[http://dx.doi.org/10.1073/pnas.94.15.8220] [PMID: 9223342]
[http://dx.doi.org/10.1089/ars.2006.8.885] [PMID: 16771678]
[http://dx.doi.org/10.1038/sj.npp.1300187] [PMID: 12784118]
[http://dx.doi.org/10.1016/S0028-3908(98)00104-X] [PMID: 9833636]
[http://dx.doi.org/10.1016/0006-291X(92)90824-5] [PMID: 1379808]
[http://dx.doi.org/10.1006/bbrc.1994.1017] [PMID: 7507317]
[http://dx.doi.org/10.1097/00001756-199412300-00029] [PMID: 7703396]
[http://dx.doi.org/10.1073/pnas.241380298] [PMID: 11717466]
[http://dx.doi.org/10.1016/0304-3940(94)90833-8] [PMID: 7514775]
[PMID: 8631633]
[http://dx.doi.org/10.1016/0896-6273(94)90349-2] [PMID: 7520253]
[http://dx.doi.org/10.1074/jbc.274.44.31185] [PMID: 10531311]
[http://dx.doi.org/10.1006/bbrc.1995.1824] [PMID: 7540837]
[http://dx.doi.org/10.1006/bbrc.1996.0008] [PMID: 8573169]
[http://dx.doi.org/10.1074/jbc.273.46.30249] [PMID: 9804784]
[http://dx.doi.org/10.1016/S0014-5793(97)01397-5] [PMID: 9428730]
[http://dx.doi.org/10.1093/biolreprod/67.1.20] [PMID: 12079995]
[http://dx.doi.org/10.1006/bbrc.1998.9578] [PMID: 9791007]
[http://dx.doi.org/10.1097/00001756-199303000-00013] [PMID: 7682853]
[http://dx.doi.org/10.1038/369061a0] [PMID: 8164740]