KEGG   PATHWAY: rno04928
Entry
rno04928                    Pathway                                
Name
Parathyroid hormone synthesis, secretion and action - Rattus norvegicus (rat)
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
rno04928  Parathyroid hormone synthesis, secretion and action
rno04928

Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24247  Casr; extracellular calcium-sensing receptor precursor [KO:K04612]
25686  Gnai1; guanine nucleotide-binding protein G(i) subunit alpha-1 [KO:K04630]
25643  Gnai3; guanine nucleotide-binding protein G(i) subunit alpha-3 [KO:K04630]
81664  Gnai2; guanine nucleotide-binding protein G(i) subunit alpha-2 [KO:K04630]
305509  Adcy1; adenylate cyclase type 1 [KO:K08041] [EC:4.6.1.1]
81636  Adcy2; adenylate cyclase type 2 [KO:K08042] [EC:4.6.1.1]
64508  Adcy3; adenylate cyclase type 3 [KO:K08043] [EC:4.6.1.1]
54223  Adcy4; adenylate cyclase type 4 [KO:K08044] [EC:4.6.1.1]
64532  Adcy5; adenylate cyclase type 5 [KO:K08045] [EC:4.6.1.1]
25289  Adcy6; adenylate cyclase type 6 isoform 2 [KO:K08046] [EC:4.6.1.1]
84420  Adcy7; adenylate cyclase type 7 [KO:K08047] [EC:4.6.1.1]
29241  Adcy8; adenylate cyclase type 8 [KO:K08048] [EC:4.6.1.1]
302950  Adcy9; adenylate cyclase type 9 [KO:K08049] [EC:4.6.1.1]
81666  Gnaq; guanine nucleotide-binding protein G(q) subunit alpha [KO:K04634]
81662  Gna11; guanine nucleotide-binding protein subunit alpha-11 [KO:K04635]
24654  Plcb1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1 [KO:K05858] [EC:3.1.4.11]
29322  Plcb3; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 [KO:K05858] [EC:3.1.4.11]
85240  Plcb2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 [KO:K05858] [EC:3.1.4.11]
25031  Plcb4; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-4 [KO:K05858] [EC:3.1.4.11]
25262  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 isoform 3 [KO:K04958]
81678  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
25679  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
29394  Gcm1; chorion-specific transcription factor GCMa [KO:K21598]
291047  Gcm2; chorion-specific transcription factor GCMb [KO:K21598]
54264  Mafb; transcription factor MafB [KO:K09036]
85471  Gata3; trans-acting T-cell-specific transcription factor GATA-3 [KO:K17895]
24790  Sp1; transcription factor Sp1 [KO:K04684]
24873  Vdr; vitamin D3 receptor [KO:K08539]
25271  Rxra; retinoic acid receptor RXR-alpha [KO:K08524]
361801  Rxrb; retinoic acid receptor RXR-beta [KO:K08525]
83574  Rxrg; retinoic acid receptor RXR-gamma [KO:K08526]
170583  Fgf23; fibroblast growth factor 23 precursor [KO:K22428]
79114  Fgfr1; fibroblast growth factor receptor 1 precursor [KO:K04362] [EC:2.7.10.1]
83504  Kl; klotho precursor [KO:K14756] [EC:3.2.1.31]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
24330  Egr1; early growth response protein 1 [KO:K09203]
24694  Pth; parathyroid hormone precursor [KO:K05261]
29517  Sgk1; serine/threonine-protein kinase Sgk1 isoform 1 [KO:K13302] [EC:2.7.11.1]
116477  Wnk1; serine/threonine-protein kinase WNK1 isoform 3 [KO:K08867] [EC:2.7.11.1]
287715  Wnk4; serine/threonine-protein kinase WNK4 [KO:K08867] [EC:2.7.11.1]
306811  Wnk2; serine/threonine-protein kinase WNK2 [KO:K08867] [EC:2.7.11.1]
317420  Wnk3; serine/threonine-protein kinase WNK3 isoform 1 [KO:K08867] [EC:2.7.11.1]
316064  Oxsr1; serine/threonine-protein kinase OSR1 [KO:K08835] [EC:2.7.11.1]
54348  Stk39; STE20/SPS1-related proline-alanine-rich protein kinase [KO:K08835] [EC:2.7.11.1]
54300  Slc12a3; solute carrier family 12 member 3 [KO:K14426]
24695  Pthlh; parathyroid hormone-related protein preproprotein [KO:K22608]
56813  Pth1r; parathyroid hormone/parathyroid hormone-related peptide receptor precursor [KO:K04585]
24680  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
25023  Prkcb; protein kinase C beta type isoform 2 [KO:K19662] [EC:2.7.11.13]
24681  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
116469  Trpv5; transient receptor potential cation channel subfamily V member 5 [KO:K04974]
25548  Slc34a1; sodium-dependent phosphate transport protein 2A [KO:K14683]
84395  Slc34a2; sodium-dependent phosphate transport protein 2B [KO:K14683]
246234  Slc34a3; sodium-dependent phosphate transport protein 2C [KO:K14683]
59114  Nherf1; Na(+)/H(+) exchange regulatory cofactor NHE-RF1 [KO:K13365]
24896  Gnas; SCG6 (secretogranin VI) isoform SCG6 precursor [KO:K04632]
25638  Pde4a; 3',5'-cyclic-AMP phosphodiesterase 4A isoform 1 [KO:K13293] [EC:3.1.4.53]
24626  Pde4b; 3',5'-cyclic-AMP phosphodiesterase 4B isoform 2 [KO:K13293] [EC:3.1.4.53]
290646  Pde4c; 3',5'-cyclic-AMP phosphodiesterase 4C [KO:K13293] [EC:3.1.4.53]
24627  Pde4d; 3',5'-cyclic-AMP phosphodiesterase 4D isoform 1 [KO:K13293] [EC:3.1.4.53]
25636  Prkaca; cAMP-dependent protein kinase catalytic subunit alpha [KO:K04345] [EC:2.7.11.11]
293508  Prkacb; cAMP-dependent protein kinase catalytic subunit beta [KO:K04345] [EC:2.7.11.11]
114700  Cyp27b1; 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial [KO:K07438] [EC:1.14.15.18]
25279  Cyp24a1; 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial precursor [KO:K07436] [EC:1.14.15.16]
309957  Mef2a; myocyte-specific enhancer factor 2A [KO:K09260]
499497  Mef2c; myocyte-specific enhancer factor 2C isoform 1 [KO:K04454]
81518  Mef2d; myocyte-specific enhancer factor 2D [KO:K09262]
80722  Sost; sclerostin precursor [KO:K16834]
54278  Nr4a2; nuclear receptor subfamily 4 group A member 2 [KO:K08558]
288770  Naca; nascent polypeptide-associated complex subunit alpha isoform 1 [KO:K03626]
24518  Jund; transcription factor JunD isoform JunD-FL [KO:K04449]
25295  Bglap; osteocalcin preproprotein [KO:K22609]
293649  Lrp5; low-density lipoprotein receptor-related protein 5 precursor [KO:K03068]
312781  Lrp6; low-density lipoprotein receptor-related protein 6 isoform 2 precursor [KO:K03068]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
81647  Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
500131  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
406169  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
117516  Tnfsf11; tumor necrosis factor ligand superfamily member 11 [KO:K05473]
24224  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
114851  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
314322  Fos; protein c-Fos [KO:K04379]
367218  Runx2; runt-related transcription factor 2 isoform 1 [KO:K09278]
171052  Mmp13; collagenase 3 precursor [KO:K07994] [EC:3.4.24.-]
81663  Gna12; guanine nucleotide-binding protein subunit alpha-12 [KO:K04346]
303634  Gna13; guanine nucleotide-binding protein subunit alpha-13 [KO:K04639]
60323  Arhgef1; rho guanine nucleotide exchange factor 1 [KO:K12330]
78966  Arhgef11; rho guanine nucleotide exchange factor 11 [KO:K12331]
293024  Akap13; A-kinase anchor protein 13 [KO:K16529]
117273  Rhoa; transforming protein RhoA [KO:K04513]
297173  RSA-14-44; ras homolog gene family, member A [KO:K04513]
25097  Pld2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
25096  Pld1; phospholipase D1 isoform 2 [KO:K01115] [EC:3.1.4.4]
25387  Arrb1; beta-arrestin-1 [KO:K04439]
25388  Arrb2; beta-arrestin-2 [KO:K04439]
64363  Araf; serine/threonine-protein kinase A-Raf isoform 1 [KO:K08845] [EC:2.7.11.1]
114486  Braf; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
81707  Mmp14; matrix metalloproteinase-14 precursor [KO:K07763] [EC:3.4.24.80]
291848  Mmp15; matrix metalloproteinase-15 precursor [KO:K07995] [EC:3.4.24.-]
65205  Mmp16; matrix metalloproteinase-16 precursor [KO:K07996] [EC:3.4.24.-]
288626  Mmp17; matrix metalloproteinase-17 precursor [KO:K07997] [EC:3.4.24.-]
83513  Mmp24; matrix metalloproteinase-24 precursor [KO:K08002] [EC:3.4.24.-]
302963  Mmp25; matrix metalloproteinase-25 [KO:K08003] [EC:3.4.24.-]
25433  Hbegf; proheparin-binding EGF-like growth factor precursor [KO:K08523]
24329  Egfr; epidermal growth factor receptor isoform 2 precursor [KO:K04361] [EC:2.7.10.1]
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
rno04012  ErbB signaling pathway
rno04020  Calcium signaling pathway
rno04024  cAMP signaling pathway
rno04310  Wnt signaling pathway
rno04380  Osteoclast differentiation
rno04961  Endocrine and other factor-regulated calcium reabsorption
KO pathway
ko04928   

  All links  
Genome (1)   
   KEGG GENOME (1)   
Gene (112)   
   KEGG GENES (112)   
All databases (113)   

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