KEGG   PATHWAY: oor04928
Entry
oor04928                    Pathway                                
Name
Parathyroid hormone synthesis, secretion and action - Orcinus orca (killer whale)
Description
Parathyroid hormone (PTH) is a key regulator of calcium and phosphorus homeostasis. The principal regulators of PTH secretion are extracellular ionized calcium (Ca2+) and 1,25-dihydroxyvitamin D (1,25(OH)2D3). Under conditions of dietary Ca restriction, a decrement in serum Ca concentration induces release of PTH from the parathyroid gland. PTH acts on bone and kidney to stimulate bone turnover, increase the circulating levels of 1,25(OH)2D3 and calcium and inhibit the reabsorption of phosphate from the glomerular filtrate. This hormone exerts its actions via binding to the PTH/PTH-related peptide receptor (PTH1R). PTH1R primarily activates two sub-types of heterotrimeric Gproteins: Gs and Gq , which in turn regulate the activity of adenylyl cyclases and phospholipase C (PLC) that control the flow of cAMP/PKA and IP/PKC signaling cascades, respectively.
Class
Organismal Systems; Endocrine system
Pathway map
oor04928  Parathyroid hormone synthesis, secretion and action
oor04928

Organism
Orcinus orca (killer whale) [GN:oor]
Gene
101269696  GNA11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
101270463  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X2 [KO:K13293] [EC:3.1.4.53]
101270492  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
101270548  PLCB1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 isoform X1 [KO:K05858] [EC:3.1.4.11]
101270600  RXRA; retinoic acid receptor RXR-alpha isoform X4 [KO:K08524]
101270961  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X1 [KO:K05858] [EC:3.1.4.11]
101271043  LRP5; low-density lipoprotein receptor-related protein 5 isoform X2 [KO:K03068]
101271151  [KO:K07436] [EC:1.14.15.16]
101271719  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
101271966  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
101272130  HBEGF; proheparin-binding EGF-like growth factor [KO:K08523]
101272184  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
101272376  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
101272573  ARHGEF11; rho guanine nucleotide exchange factor 11 isoform X5 [KO:K12331]
101272925  SLC34A2; sodium-dependent phosphate transport protein 2B [KO:K14683]
101272984  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
101273023  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
101273041  PTH; parathyroid hormone isoform X1 [KO:K05261]
101273115  TRPV5; transient receptor potential cation channel subfamily V member 5 [KO:K04974]
101273160  MEF2C; myocyte-specific enhancer factor 2C isoform X1 [KO:K04454]
101273171  ADCY8; adenylate cyclase type 8 isoform X1 [KO:K08048] [EC:4.6.1.1]
101273287  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
101273592  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
101273605  ATF6B; LOW QUALITY PROTEIN: cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
101273830  RHOA; transforming protein RhoA [KO:K04513]
101273911  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
101274558  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
101274903  GCM1; chorion-specific transcription factor GCMa [KO:K21598]
101275099  MMP17; matrix metalloproteinase-17 isoform X2 [KO:K07997] [EC:3.4.24.-]
101275122  EGR1; early growth response protein 1 [KO:K09203]
101275398  EGFR; epidermal growth factor receptor isoform X2 [KO:K04361] [EC:2.7.10.1]
101276079  RUNX2; runt-related transcription factor 2 isoform X1 [KO:K09278]
101276297  KL; klotho [KO:K14756] [EC:3.2.1.31]
101276350  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
101276408  SLC34A3; sodium-dependent phosphate transport protein 2C isoform X13 [KO:K14683]
101276418  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
101276500  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
101276750  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
101276923  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X2 [KO:K04450]
101277002  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
101277195  BRAF; serine/threonine-protein kinase B-raf isoform X4 [KO:K04365] [EC:2.7.11.1]
101277316  PTH1R; parathyroid hormone/parathyroid hormone-related peptide receptor [KO:K04585]
101277471  GNAI3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
101277558  SLC12A3; solute carrier family 12 member 3 [KO:K14426]
101277736  SLC34A1; sodium-dependent phosphate transport protein 2A [KO:K14683]
101277834  PTHLH; parathyroid hormone-related protein [KO:K22608]
101277927  VDR; vitamin D3 receptor isoform X3 [KO:K08539]
101277931  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
101277939  OXSR1; serine/threonine-protein kinase OSR1 isoform X1 [KO:K08835] [EC:2.7.11.1]
101278368  ADCY1; adenylate cyclase type 1 isoform X1 [KO:K08041] [EC:4.6.1.1]
101278706  PLD2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
101278779  MEF2D; myocyte-specific enhancer factor 2D isoform X1 [KO:K09262]
101278828  [KO:K13293] [EC:3.1.4.53]
101278980  NACA; nascent polypeptide-associated complex subunit alpha isoform X3 [KO:K03626]
101279087  GATA3; trans-acting T-cell-specific transcription factor GATA-3 isoform X1 [KO:K17895]
101279623  FGFR1; fibroblast growth factor receptor 1 isoform X3 [KO:K04362] [EC:2.7.10.1]
101279717  ARHGEF1; rho guanine nucleotide exchange factor 1 isoform X1 [KO:K12330]
101279781  [KO:K04634]
101280083  JUND; transcription factor JunD [KO:K04449]
101280331  PDE4C; cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
101280397  MEF2A; myocyte-specific enhancer factor 2A isoform X4 [KO:K09260]
101280659  MAFB; transcription factor MafB [KO:K09036]
101280858  ARRB1; beta-arrestin-1 isoform X1 [KO:K04439]
101280894  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
101281043  SGK1; serine/threonine-protein kinase Sgk1 isoform X1 [KO:K13302] [EC:2.7.11.1]
101281075  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
101281155  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
101281359  GCM2; chorion-specific transcription factor GCMb [KO:K21598]
101281417  PLCB2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 isoform X9 [KO:K05858] [EC:3.1.4.11]
101281525  FGF23; fibroblast growth factor 23 [KO:K22428]
101281654  ADCY9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
101281808  STK39; STE20/SPS1-related proline-alanine-rich protein kinase isoform X1 [KO:K08835] [EC:2.7.11.1]
101281876  BGLAP; LOW QUALITY PROTEIN: osteocalcin [KO:K22609]
101282737  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X2 [KO:K04958]
101282939  [KO:K04632]
101283178  ADCY5; adenylate cyclase type 5 isoform X2 [KO:K08045] [EC:4.6.1.1]
101283438  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
101283651  ADCY3; adenylate cyclase type 3 isoform X1 [KO:K08043] [EC:4.6.1.1]
101283835  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
101283840  MMP24; matrix metalloproteinase-24 [KO:K08002] [EC:3.4.24.-]
101284082  PLD1; phospholipase D1 isoform X6 [KO:K01115] [EC:3.1.4.4]
101284262  [KO:K07438] [EC:1.14.15.18]
101284377  MMP15; matrix metalloproteinase-15 [KO:K07995] [EC:3.4.24.-]
101284480  SOST; sclerostin [KO:K16834]
101284508  SP1; transcription factor Sp1 isoform X1 [KO:K04684]
101284790  MMP14; matrix metalloproteinase-14 [KO:K07763] [EC:3.4.24.80]
101284929  TNFSF11; tumor necrosis factor ligand superfamily member 11 [KO:K05473]
101284966  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
101285712  NHERF1; Na(+)/H(+) exchange regulatory cofactor NHE-RF1 [KO:K13365]
101286059  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B isoform X1 [KO:K13293] [EC:3.1.4.53]
101286207  ADCY2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
101286253  WNK3; serine/threonine-protein kinase WNK3 [KO:K08867] [EC:2.7.11.1]
101286338  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform X3 [KO:K09048]
101286388  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101286650  FOS; protein c-Fos [KO:K04379]
101286834  [KO:K04632]
101286903  MMP16; matrix metalloproteinase-16 [KO:K07996] [EC:3.4.24.-]
101286926  WNK4; serine/threonine-protein kinase WNK4 [KO:K08867] [EC:2.7.11.1]
101287219  MMP25; matrix metalloproteinase-25 isoform X1 [KO:K08003] [EC:3.4.24.-]
101287304  RXRB; retinoic acid receptor RXR-beta isoform X4 [KO:K08525]
101287404  [KO:K03626]
101287411  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 isoform X2 [KO:K09048]
101287666  NR4A2; nuclear receptor subfamily 4 group A member 2 isoform X1 [KO:K08558]
101287685  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X2 [KO:K05870]
101288384  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
101289047  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X4 [KO:K09047]
101289190  LRP6; low-density lipoprotein receptor-related protein 6 isoform X2 [KO:K03068]
101289265  [KO:K03626]
101289285  RXRG; retinoic acid receptor RXR-gamma isoform X1 [KO:K08526]
101289394  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101289504  CASR; extracellular calcium-sensing receptor [KO:K04612]
101289534  AKAP13; A-kinase anchor protein 13 isoform X4 [KO:K16529]
101289858  ADCY4; adenylate cyclase type 4 isoform X2 [KO:K08044] [EC:4.6.1.1]
101290180  WNK2; serine/threonine-protein kinase WNK2 isoform X1 [KO:K08867] [EC:2.7.11.1]
101290326  WNK1; serine/threonine-protein kinase WNK1 isoform X2 [KO:K08867] [EC:2.7.11.1]
125962100  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
Compound
C00009  Orthophosphate
C00020  AMP
C00076  Calcium cation
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
C00698  Cl-
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C01561  Calcidiol
C01673  Calcitriol
C18231  Calcitetrol
Reference
PMID:27065162
  Authors
Khundmiri SJ, Murray RD, Lederer E
  Title
PTH and Vitamin D.
  Journal
Compr Physiol 6:561-601 (2016)
DOI:10.1002/cphy.c140071
Reference
PMID:28363951
  Authors
Bastepe M, Turan S, He Q
  Title
Heterotrimeric G proteins in the control of parathyroid hormone actions.
  Journal
J Mol Endocrinol 58:R203-R224 (2017)
DOI:10.1530/JME-16-0221
Reference
PMID:20703892
  Authors
Vilardaga JP, Romero G, Friedman PA, Gardella TJ
  Title
Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm.
  Journal
Cell Mol Life Sci 68:1-13 (2011)
DOI:10.1007/s00018-010-0465-9
Reference
PMID:29291826
  Authors
Naveh-Many T, Silver J
  Title
Transcription factors that determine parathyroid development power PTH expression.
  Journal
Kidney Int 93:7-9 (2018)
DOI:10.1016/j.kint.2017.08.026
Reference
PMID:25917456
  Authors
Han SI, Tsunekage Y, Kataoka K
  Title
Gata3 cooperates with Gcm2 and MafB to activate parathyroid hormone gene expression by interacting with SP1.
  Journal
Mol Cell Endocrinol 411:113-20 (2015)
DOI:10.1016/j.mce.2015.04.018
Reference
PMID:22622503
  Authors
Ferre S, Hoenderop JG, Bindels RJ
  Title
Sensing mechanisms involved in Ca2+ and Mg2+ homeostasis.
  Journal
Kidney Int 82:1157-66 (2012)
DOI:10.1038/ki.2012.179
Reference
PMID:20010546
  Authors
Komaba H, Fukagawa M
  Title
FGF23-parathyroid interaction: implications in chronic kidney disease.
  Journal
Kidney Int 77:292-8 (2010)
DOI:10.1038/ki.2009.466
Reference
PMID:27194212
  Authors
Bilezikian JP, Cusano NE, Khan AA, Liu JM, Marcocci C, Bandeira F
  Title
Primary hyperparathyroidism.
  Journal
Nat Rev Dis Primers 2:16033 (2016)
DOI:10.1038/nrdp.2016.33
Reference
PMID:21576356
  Authors
de Groot T, Kovalevskaya NV, Verkaart S, Schilderink N, Felici M, van der Hagen EA, Bindels RJ, Vuister GW, Hoenderop JG
  Title
Molecular mechanisms of calmodulin action on TRPV5 and modulation by parathyroid hormone.
  Journal
Mol Cell Biol 31:2845-53 (2011)
DOI:10.1128/MCB.01319-10
Reference
PMID:17975663
  Authors
Hernando N, Wagner C, Biber J, Murer H
  Title
Kidney kinase network regulates renal ion cotransport.
  Journal
J Clin Invest 117:3179-82 (2007)
DOI:10.1172/JCI33859
Reference
PMID:22628548
  Authors
Wang B, Means CK, Yang Y, Mamonova T, Bisello A, Altschuler DL, Scott JD, Friedman PA
  Title
Ezrin-anchored protein kinase A coordinates phosphorylation-dependent disassembly of a NHERF1 ternary complex to regulate hormone-sensitive phosphate transport.
  Journal
J Biol Chem 287:24148-63 (2012)
DOI:10.1074/jbc.M112.369405
Reference
PMID:21097685
  Authors
Crenshaw TD, Rortvedt LA, Hassen Z
  Title
Triennial Growth Symposium: a novel pathway for vitamin D-mediated phosphate homeostasis: implications for skeleton growth and mineralization.
  Journal
J Anim Sci 89:1957-64 (2011)
DOI:10.2527/jas.2010-3411
Reference
PMID:11698670
  Authors
Zierold C, Mings JA, DeLuca HF
  Title
Parathyroid hormone regulates 25-hydroxyvitamin D(3)-24-hydroxylase mRNA by altering its stability.
  Journal
Proc Natl Acad Sci U S A 98:13572-6 (2001)
DOI:10.1073/pnas.241516798
Reference
PMID:20074973
  Authors
Kramer I, Keller H, Leupin O, Kneissel M
  Title
Does osteocytic SOST suppression mediate PTH bone anabolism?
  Journal
Trends Endocrinol Metab 21:237-44 (2010)
DOI:10.1016/j.tem.2009.12.002
Reference
PMID:17696759
  Authors
Leupin O, Kramer I, Collette NM, Loots GG, Natt F, Kneissel M, Keller H
  Title
Control of the SOST bone enhancer by PTH using MEF2 transcription factors.
  Journal
J Bone Miner Res 22:1957-67 (2007)
DOI:10.1359/jbmr.070804
Reference
PMID:24940803
  Authors
Meir T, Durlacher K, Pan Z, Amir G, Richards WG, Silver J, Naveh-Many T
  Title
Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription.
  Journal
Kidney Int 86:1106-15 (2014)
DOI:10.1038/ki.2014.215
Reference
PMID:29413898
  Authors
Pellicelli M, Hariri H, Miller JA, St-Arnaud R
  Title
Lrp6 is a target of the PTH-activated alphaNAC transcriptional coregulator.
  Journal
Biochim Biophys Acta 1861:61-71 (2018)
DOI:10.1016/j.bbagrm.2018.01.008
Reference
PMID:12364326
  Authors
Fu Q, Jilka RL, Manolagas SC, O'Brien CA
  Title
Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein.
  Journal
J Biol Chem 277:48868-75 (2002)
DOI:10.1074/jbc.M208494200
Reference
PMID:19716455
  Authors
O'Brien CA
  Title
Control of RANKL gene expression.
  Journal
Bone 46:911-9 (2010)
DOI:10.1016/j.bone.2009.08.050
Reference
PMID:17517365
  Authors
Jilka RL
  Title
Molecular and cellular mechanisms of the anabolic effect of intermittent PTH.
  Journal
Bone 40:1434-46 (2007)
DOI:10.1016/j.bone.2007.03.017
Reference
PMID:8810350
  Authors
Pearman AT, Chou WY, Bergman KD, Pulumati MR, Partridge NC
  Title
Parathyroid hormone induces c-fos promoter activity in osteoblastic cells through phosphorylated cAMP response element (CRE)-binding protein binding to the major CRE.
  Journal
J Biol Chem 271:25715-21 (1996)
DOI:10.1074/jbc.271.41.25715
Reference
PMID:16164977
  Authors
Boumah CE, Selvamurugan N, Partridge NC
  Title
Transcription in the osteoblast: regulatory mechanisms utilized by parathyroid hormone and transforming growth factor-beta.
  Journal
Prog Nucleic Acid Res Mol Biol 80:287-321 (2005)
DOI:10.1016/S0079-6603(05)80007-8
Reference
PMID:11274169
  Authors
Hess J, Porte D, Munz C, Angel P
  Title
AP-1 and Cbfa/runt physically interact and regulate parathyroid hormone-dependent MMP13 expression in osteoblasts through a new osteoblast-specific element 2/AP-1  composite element.
  Journal
J Biol Chem 276:20029-38 (2001)
DOI:10.1074/jbc.M010601200
Reference
PMID:15705779
  Authors
Singh AT, Gilchrist A, Voyno-Yasenetskaya T, Radeff-Huang JM, Stern PH
  Title
G alpha12/G alpha13 subunits of heterotrimeric G proteins mediate parathyroid hormone activation of phospholipase D in UMR-106 osteoblastic cells.
  Journal
Endocrinology 146:2171-5 (2005)
DOI:10.1210/en.2004-1283
Reference
PMID:12738761
  Authors
Ahmed I, Gesty-Palmer D, Drezner MK, Luttrell LM
  Title
Transactivation of the epidermal growth factor receptor mediates parathyroid hormone and prostaglandin F2 alpha-stimulated mitogen-activated protein kinase activation in cultured transgenic murine osteoblasts.
  Journal
Mol Endocrinol 17:1607-21 (2003)
DOI:10.1210/me.2002-0040
Reference
PMID:17107942
  Authors
Sneddon WB, Yang Y, Ba J, Harinstein LM, Friedman PA
  Title
Extracellular signal-regulated kinase activation by parathyroid hormone in distal tubule cells.
  Journal
Am J Physiol Renal Physiol 292:F1028-34 (2007)
DOI:10.1152/ajprenal.00288.2006
Reference
PMID:32982979
  Authors
Agoro R, Ni P, Noonan ML, White KE
  Title
Osteocytic FGF23 and Its Kidney Function.
  Journal
Front Endocrinol (Lausanne) 11:592 (2020)
DOI:10.3389/fendo.2020.00592
Reference
PMID:27622885
  Authors
Erben RG, Andrukhova O
  Title
FGF23-Klotho signaling axis in the kidney.
  Journal
Bone 100:62-68 (2017)
DOI:10.1016/j.bone.2016.09.010
Reference
PMID:33491560
  Authors
Murillo-de-Ozores AR, Rodriguez-Gama A, Carbajal-Contreras H, Gamba G, Castaneda-Bueno M
  Title
WNK4 kinase: from structure to physiology.
  Journal
Am J Physiol Renal Physiol 320:F378-F403 (2021)
DOI:10.1152/ajprenal.00634.2020
Related
pathway
oor04012  ErbB signaling pathway
oor04020  Calcium signaling pathway
oor04024  cAMP signaling pathway
oor04310  Wnt signaling pathway
oor04380  Osteoclast differentiation
oor04961  Endocrine and other factor-regulated calcium reabsorption
KO pathway
ko04928   

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