KEGG PATHWAY: ko04928

PATHWAY: ko04928

Entry

ko04928                     Pathway

Name

Parathyroid hormone synthesis, secretion and action

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

ko04928

Parathyroid hormone synthesis, secretion and action

Orthology

K04612

calcium-sensing receptor

K04630

guanine nucleotide-binding protein G(i) subunit alpha

K08041

adenylate cyclase 1 [EC:4.6.1.1]

K08042

adenylate cyclase 2 [EC:4.6.1.1]

K08043

adenylate cyclase 3 [EC:4.6.1.1]

K08044

adenylate cyclase 4 [EC:4.6.1.1]

K08045

adenylate cyclase 5 [EC:4.6.1.1]

K08046

adenylate cyclase 6 [EC:4.6.1.1]

K08047

adenylate cyclase 7 [EC:4.6.1.1]

K08048

adenylate cyclase 8 [EC:4.6.1.1]

K08049

adenylate cyclase 9 [EC:4.6.1.1]

K04634

guanine nucleotide-binding protein G(q) subunit alpha

K04635

guanine nucleotide-binding protein subunit alpha-11

K05858

phosphatidylinositol phospholipase C, beta [EC:3.1.4.11]

K04958

inositol 1,4,5-triphosphate receptor type 1

K04959

inositol 1,4,5-triphosphate receptor type 2

K04960

inositol 1,4,5-triphosphate receptor type 3

K21598

chorion-specific transcription factor GCM

K09036

transcription factor MAFB

K17895

GATA-binding protein 3

K04684

transcription factor Sp1

K08539

vitamin D3 receptor

K08524

retinoid X receptor alpha

K08525

retinoid X receptor beta

K08526

retinoid X receptor gamma

K22428

fibroblast growth factor 23

K04362

fibroblast growth factor receptor 1 [EC:2.7.10.1]

K14756

klotho [EC:3.2.1.31]

K04371

mitogen-activated protein kinase 1/3 [EC:2.7.11.24]

K09203

early growth response protein 1

K05261

parathyroid hormone

K13302

serum/glucocorticoid-regulated kinase 1 [EC:2.7.11.1]

K08867

WNK lysine deficient protein kinase [EC:2.7.11.1]

K08835

serine/threonine-protein kinase OSR1/STK39 [EC:2.7.11.1]

K14426

solute carrier family 12 (sodium/chloride transporter), member 3

K22608

parathyroid hormone-related hormone

K04585

parathyroid hormone receptor 1

K02677

classical protein kinase C alpha type [EC:2.7.11.13]

K19662

classical protein kinase C beta type [EC:2.7.11.13]

K19663

classical protein kinase C gamma type [EC:2.7.11.13]

K04974

transient receptor potential cation channel subfamily V member 5

K14683

solute carrier family 34 (sodium-dependent phosphate cotransporter)

K13365

sodium/hydrogen exchange regulatory cofactor NHE-RF1

K04632

guanine nucleotide-binding protein G(s) subunit alpha

K13293

cAMP-specific phosphodiesterase 4 [EC:3.1.4.53]

K04345

protein kinase A [EC:2.7.11.11]

K07438

calcidiol 1-monooxygenase (25-hydroxyvitamin D3 1alpha-hydroxylase) [EC:1.14.15.18]

K07436

vitamin D3 24-hydroxylase [EC:1.14.15.16]

K09260

MADS-box transcription enhancer factor 2A

K04454

MADS-box transcription enhancer factor 2C

K09262

MADS-box transcription enhancer factor 2D

K16834

sclerostin

K08558

nuclear receptor subfamily 4 group A member 2

K03626

nascent polypeptide-associated complex subunit alpha

K04449

transcription factor jun-D

K22609

osteocalcin

K03068

low density lipoprotein receptor-related protein 5/6

K05870

cyclic AMP-responsive element-binding protein 1

K04450

cyclic AMP-dependent transcription factor ATF-2

K09048

cyclic AMP-responsive element-binding protein 3

K04374

cyclic AMP-dependent transcription factor ATF-4

K09047

cyclic AMP-responsive element-binding protein 5

K09049

cyclic AMP-dependent transcription factor ATF-6 beta

K05473

tumor necrosis factor ligand superfamily member 11

K02161

apoptosis regulator Bcl-2

K06625

cyclin-dependent kinase inhibitor 1A

K04379

proto-oncogene protein c-fos

K09278

runt-related transcription factor 2

K07994

matrix metalloproteinase-13 (collagenase 3) [EC:3.4.24.-]

K04346

guanine nucleotide-binding protein subunit alpha-12

K04639

guanine nucleotide-binding protein subunit alpha-13

K12330

Rho guanine nucleotide exchange factor 1

K12331

Rho guanine nucleotide exchange factor 11

K16529

A-kinase anchor protein 13

K04513

Ras homolog gene family, member A

K01115

phospholipase D1/2 [EC:3.1.4.4]

K04439

beta-arrestin

K08845

A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04365

B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04366

RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]

K04368

mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]

K07763

matrix metalloproteinase-14 (membrane-inserted) [EC:3.4.24.80]

K07995

matrix metalloproteinase-15 (membrane-inserted) [EC:3.4.24.-]

K07996

matrix metalloproteinase-16 (membrane-inserted) [EC:3.4.24.-]

K07997

matrix metalloproteinase-17 (membrane-inserted) [EC:3.4.24.-]

K08002

matrix metalloproteinase-24 (membrane-inserted) [EC:3.4.24.-]

K08003

matrix metalloproteinase-25 (membrane-inserted) [EC:3.4.24.-]

K08523

heparin-binding EGF-like growth factor

K04361

epidermal growth factor receptor [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