KEGG   PATHWAY: lav04928
Entry
lav04928                    Pathway                                

Name
Parathyroid hormone synthesis, secretion and action - Loxodonta africana (African savanna elephant)
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
lav04928  Parathyroid hormone synthesis, secretion and action
lav04928

Organism
Loxodonta africana (African savanna elephant) [GN:lav]
Gene
100671950  CASR; extracellular calcium-sensing receptor isoform X2 [KO:K04612]
100666344  GNAI1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
100670234  GNAI2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
100667957  GNAI3; LOW QUALITY PROTEIN: guanine nucleotide-binding protein G(k) subunit alpha [KO:K04630]
100671072  ADCY1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
100673570  ADCY2; LOW QUALITY PROTEIN: adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
100674724  ADCY3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
100675525  ADCY4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
100670244  ADCY5; LOW QUALITY PROTEIN: adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
100653532  ADCY6; adenylate cyclase type 6 isoform X1 [KO:K08046] [EC:4.6.1.1]
100653771  ADCY7; adenylate cyclase type 7 isoform X1 [KO:K08047] [EC:4.6.1.1]
100661616  ADCY8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
100663448  ADCY9; LOW QUALITY PROTEIN: adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
100656672  GNAQ; guanine nucleotide-binding protein G(q) subunit alpha isoform X1 [KO:K04634]
100675896  guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
100670617  PLCB4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 isoform X3 [KO:K05858] [EC:3.1.4.11]
100672435  PLCB1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
100668575  PLCB2; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
100663829  PLCB3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 isoform X1 [KO:K05858] [EC:3.1.4.11]
100665028  ITPR1; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
100667845  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
100659666  ITPR3; LOW QUALITY PROTEIN: inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
100669901  GCM1; chorion-specific transcription factor GCMa [KO:K21598]
100677100  GCM2; chorion-specific transcription factor GCMb [KO:K21598]
104846049  MAFB; transcription factor MafB [KO:K09036]
100655161  GATA3; LOW QUALITY PROTEIN: trans-acting T-cell-specific transcription factor GATA-3 [KO:K17895]
100662543  SP1; transcription factor Sp1 [KO:K04684]
100675066  VDR; vitamin D3 receptor isoform X2 [KO:K08539]
100674208  retinoic acid receptor RXR-alpha-like [KO:K08524]
100662699  RXRB; retinoic acid receptor RXR-beta isoform X2 [KO:K08525]
100653765  RXRG; retinoic acid receptor RXR-gamma [KO:K08526]
100668635  FGF23; fibroblast growth factor 23 [KO:K22428]
100662289  FGFR1; fibroblast growth factor receptor 1 isoform X3 [KO:K04362] [EC:2.7.10.1]
100669095  KL; klotho [KO:K14756] [EC:3.2.1.31]
100658240  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100665157  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100671811  EGR1; early growth response protein 1 [KO:K09203]
100674622  PTH; parathyroid hormone [KO:K05261]
100670398  PTHLH; parathyroid hormone-related protein isoform X1 [KO:K22608]
100656495  PTH1R; parathyroid hormone/parathyroid hormone-related peptide receptor isoform X1 [KO:K04585]
100665736  ARRB1; beta-arrestin-1 isoform X6 [KO:K04439]
100660311  ARRB2; beta-arrestin-2 isoform X1 [KO:K04439]
100671404  ARAF; serine/threonine-protein kinase A-Raf isoform X3 [KO:K08845] [EC:2.7.11.1]
100664119  BRAF; serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
100655727  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100667623  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100665537  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100672078  PRKCB; LOW QUALITY PROTEIN: protein kinase C beta type [KO:K19662] [EC:2.7.11.13]
100671733  PRKCG; LOW QUALITY PROTEIN: protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100669535  TRPV5; transient receptor potential cation channel subfamily V member 5 [KO:K04974]
100673627  SLC34A1; sodium-dependent phosphate transport protein 2A [KO:K14683]
100666257  sodium-dependent phosphate transport protein 2B-like [KO:K14683]
100656404  sodium-dependent phosphate transport protein 2B-like [KO:K14683]
100676938  sodium-dependent phosphate transport protein 2B-like isoform X2 [KO:K14683]
100655246  SLC34A3; sodium-dependent phosphate transport protein 2C [KO:K14683]
100657092  SLC9A3R1; Na(+)/H(+) exchange regulatory cofactor NHE-RF1 isoform X1 [KO:K13365]
100655206  guanine nucleotide-binding protein G(s) subunit alpha isoform X1 [KO:K04632]
100669226  neuroendocrine secretory protein 55-like [KO:K04632]
100656573  PDE4D; cAMP-specific 3',5'-cyclic phosphodiesterase 4D isoform X2 [KO:K13293] [EC:3.1.4.53]
100667499  PDE4B; cAMP-specific 3',5'-cyclic phosphodiesterase 4B [KO:K13293] [EC:3.1.4.53]
100671572  PDE4C; LOW QUALITY PROTEIN: cAMP-specific 3',5'-cyclic phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
100671668  PDE4A; cAMP-specific 3',5'-cyclic phosphodiesterase 4A [KO:K13293] [EC:3.1.4.53]
100656966  PRKACB; cAMP-dependent protein kinase catalytic subunit beta isoform X1 [KO:K04345] [EC:2.7.11.11]
100674245  PRKACA; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
100657886  25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial [KO:K07438] [EC:1.14.15.18]
100663262  1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial [KO:K07436] [EC:1.14.15.16]
100655934  MEF2A; myocyte-specific enhancer factor 2A isoform X1 [KO:K09260]
100656767  MEF2C; myocyte-specific enhancer factor 2C isoform X1 [KO:K04454]
100671016  MEF2D; myocyte-specific enhancer factor 2D [KO:K09262]
100655563  SOST; sclerostin [KO:K16834]
100655238  NR4A2; nuclear receptor subfamily 4 group A member 2 isoform X4 [KO:K08558]
100674014  NACA; nascent polypeptide-associated complex subunit alpha [KO:K03626]
100670448  BGLAP; osteocalcin [KO:K22609]
100658734  LRP6; LOW QUALITY PROTEIN: low-density lipoprotein receptor-related protein 6 [KO:K03068]
100666209  LRP5; LOW QUALITY PROTEIN: low-density lipoprotein receptor-related protein 5 [KO:K03068]
100675162  CREB1; cyclic AMP-responsive element-binding protein 1 isoform X1 [KO:K05870]
100657989  ATF2; cyclic AMP-dependent transcription factor ATF-2 isoform X1 [KO:K04450]
100653565  CREB3L1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
100673694  CREB3L4; cyclic AMP-responsive element-binding protein 3-like protein 4 [KO:K09048]
100666211  CREB3L2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
100670574  CREB3L3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
100677344  CREB3; cyclic AMP-responsive element-binding protein 3 isoform X1 [KO:K09048]
100662521  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X2 [KO:K04374]
100675079  CREB5; cyclic AMP-responsive element-binding protein 5 isoform X1 [KO:K09047]
100666885  ATF6B; cyclic AMP-dependent transcription factor ATF-6 beta isoform X2 [KO:K09049]
100663523  TNFSF11; tumor necrosis factor ligand superfamily member 11 [KO:K05473]
100675268  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
100671706  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100674799  FOS; LOW QUALITY PROTEIN: proto-oncogene c-Fos [KO:K04379]
100658815  RUNX2; runt-related transcription factor 2 isoform X4 [KO:K09278]
100660883  MMP13; collagenase 3 [KO:K07994] [EC:3.4.24.-]
100676444  GNA12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
100664965  GNA13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
100674589  ARHGEF1; rho guanine nucleotide exchange factor 1 isoform X2 [KO:K12330]
100673301  ARHGEF11; rho guanine nucleotide exchange factor 11 isoform X1 [KO:K12331]
100677568  AKAP13; LOW QUALITY PROTEIN: A-kinase anchor protein 13 [KO:K16529]
100677447  RHOA; transforming protein RhoA [KO:K04513]
100660595  PLD1; phospholipase D1 isoform X2 [KO:K01115] [EC:3.1.4.4]
100658318  PLD2; LOW QUALITY PROTEIN: phospholipase D2 [KO:K01115] [EC:3.1.4.4]
100671131  MMP14; matrix metalloproteinase-14 [KO:K07763] [EC:3.4.24.80]
100674357  MMP15; matrix metalloproteinase-15 [KO:K07995] [EC:3.4.24.-]
100662936  MMP16; matrix metalloproteinase-16 [KO:K07996] [EC:3.4.24.-]
100676839  MMP17; LOW QUALITY PROTEIN: matrix metalloproteinase-17 [KO:K07997] [EC:3.4.24.-]
100667595  MMP24; matrix metalloproteinase-24 [KO:K08002] [EC:3.4.24.-]
100656333  MMP25; matrix metalloproteinase-25 [KO:K08003] [EC:3.4.24.-]
100675899  HBEGF; proheparin-binding EGF-like growth factor isoform X2 [KO:K08523]
100659125  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
Compound
C00009  Orthophosphate
C00020  AMP
C00076  Calcium cation
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C01561  Calcidiol
C01673  Calcitriol
C18231  Calcitetrol
Reference
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
Related
pathway
lav04012  ErbB signaling pathway
lav04020  Calcium signaling pathway
lav04024  cAMP signaling pathway
lav04310  Wnt signaling pathway
lav04380  Osteoclast differentiation
lav04961  Endocrine and other factor-regulated calcium reabsorption
KO pathway
ko04928   
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