Top ▲
Gene and Protein Information  |
|||||||
| Species | TM | P Loops | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 6 | 1 | 968 | 4q22.1 | PKD2 | polycystin 2, transient receptor potential cation channel | 15 |
| Mouse | 6 | 1 | 966 | 5 50.68 cM | Pkd2 | polycystin 2, transient receptor potential cation channel | 20,31 |
| Rat | 6 | 1 | 915 | 14q22 | Pkd2 | polycystin 2, transient receptor potential cation channel | |
| Previous and Unofficial Names |
| APKD2 | PKD2 | TRPP2 | transient receptor potential cation channel, subfamily P, member 2 | polycystic kidney disease 2 (autosomal dominant) | polycystin 2, transient receptor potential cation channel |
| Database Links |
|
| Alphafold | Q13563 (Hs), O35245 (Mm) |
| ChEMBL Target | CHEMBL5465 (Hs) |
| Ensembl Gene | ENSG00000118762 (Hs), ENSMUSG00000034462 (Mm), ENSRNOG00000002146 (Rn) |
| Entrez Gene | 5133 (Hs), 18764 (Mm), 353503 (Rn) |
| Human Protein Atlas | ENSG00000118762 (Hs) |
| KEGG Gene | hsa:5133 (Hs), mmu:18764 (Mm), rno:353503 (Rn) |
| OMIM | 173910 (Hs) |
| Orphanet | ORPHA117849 (Hs) |
| Pharos | Q13563 (Hs) |
| RefSeq Nucleotide | NM_000297 (Hs), NM_008861 (Mm), NM_001191934 (Rn) |
| RefSeq Protein | NP_000288 (Hs), NP_032887 (Mm), NP_001178863 (Rn) |
| UniProtKB | Q13563 (Hs), O35245 (Mm) |
| Wikipedia | PKD2 (Hs) |
| Associated Proteins |
||||||||||||||||||||||||||||||||
|
|
|
||||||||||||||||||||||||||||||
| Associated Protein Comments | ||||||||||||||||||||||||||||||||
| PKD1 activates the JAK-STAT pathway, upregulating p21 (waf1) to arrest the cell cycle. Mutations disrupting the interaction between TRPP1 and PKD1 prevent the activation of this pathway and could explain why disruption of either gene leads to abnormal growth [2]. | ||||||||||||||||||||||||||||||||
| Functional Characteristics |
|
| TRPP1 (PKD2) forms a cation channel (as a homomer consisting of 4 PKD2 subunits or as a heteromer combining 3 PKD2 subunits with one PKD1 subunit) that is expressed on primary cilia of kidney epithelial cells [13]. In kidney epithelial cells TRPP1 is only functional in the ciliary membrane, but not in the plasma membrane. In oocyte overexpression TRPP1 forms functional homomeric and heteromeric channels. Gain of function mutations in TRPP1 in either the S4-S5 linker (F604P) or in the lower gate (L677A, N681A) result in constitutively active channels [1,5,28]. TRPP1 prefers monovalent cations over divalent cations in the order of K+>Na+>Ca2+ (permeability 1:0.4:0.025), showing low selectivity for Ca2+. The conductance of TRPP1 varies depending on the ion (K+ : 144 pS, Na+: 89 pS, Ca2+: 4pS) [13]. TRPP1 homomeric channel produces a larger conductance of 82 pS than the PC-1/TRPP1 heteromeric channel (79.5 pS) with higher absolute open probability (TRPP1 homomeric channel: 0.58, PC-1/TRPP1 heteromeric channel: 0.08) in primary cilia [5]. Specific activators or channel blockers of TRPP1 remain unknown. | |
| Ion Selectivity and Conductance |
||||||
|
||||||
|
| Voltage Dependence |
||||||||||||||||
|
||||||||||||||||
| Voltage Dependence Comments | ||||||||||||||||
| There are few reports of current recorded from cells heterologously expressing TRPP1 alone, or in combination with PKD1. The electrophysiological properties of TRPP1 are not well established and there is disagreement as to whether measured current represent TRPP2. There are also reports that the protien is restricted to cilia in primary cells [19] and to intracellualr membranes [14] , where electrophysiological properties cannot be measured in situ with current techniques. Thus there is uncertainty about the above properties if the putative channel. If the currents do represent TRPP1, it is weakly voltage-sensitive. |
Download all structure-activity data for this target as a CSV file 
| Activators | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Activator Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Activity of TRPP1 is also affected by pH in a manner that indicates the presence of an H+ ion regulatory site on the cytoplasmic side of the protein [4] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Channel Blockers | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Channel Blocker Comments | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The TRPP1 current has not been uniquely identified therefore the channel blockers are putative. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Tissue Distribution
|
||||||||
|
||||||||
|
||||||||
|
||||||||
|
| Functional Assay Comments |
| No functional assays are available as there is no definitive demonstration that the currents described so far are via the TRPP1 channel pore, nor are there molecules that specifically activate or block TRPP1. |
| Physiological Consequences of Altering Gene Expression
|
||||||||||
|
||||||||||
| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| It is proposed that the cyst formation in heterozygotes requires a "two-hit" mechanism, where the germ-line mutation is followed by a somatic mutation leading to local homozygousity and cyst formation [30]. Increased severity of cyst formation can be seen in mice heterozygous for mutations in both TRPP1 and PKD1 [32]. | ||||||||||
| Phenotypes, Alleles and Disease Models
|
Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinically-Relevant Mutations and Pathophysiology
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1. Arif Pavel M, Lv C, Ng C, Yang L, Kashyap P, Lam C, Valentino V, Fung HY, Campbell T, Møller SG et al.. (2016) Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant. Proc Natl Acad Sci U S A, 113 (17): E2363-72. [PMID:27071085]
2. Bhunia AK, Piontek K, Boletta A, Liu L, Qian F, Xu PN, Germino FJ, Germino GG. (2002) PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell, 109 (2): 157-68. [PMID:12007403]
3. Gallagher AR, Cedzich A, Gretz N, Somlo S, Witzgall R. (2000) The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton. Proc Natl Acad Sci USA, 97 (8): 4017-22. [PMID:10760273]
4. Gonzalez-Perrett S, Batelli M, Kim K, Essafi M, Timpanaro G, Moltabetti N, Reisin IL, Arnaout MA, Cantiello HF. (2002) Voltage dependence and pH regulation of human polycystin-2-mediated cation channel activity. J Biol Chem, 277 (28): 24959-66. [PMID:11991947]
5. Ha K, Nobuhara M, Wang Q, Walker RV, Qian F, Schartner C, Cao E, Delling M. (2020) The heteromeric PC-1/PC-2 polycystin complex is activated by the PC-1 N-terminus. Elife, 9. [PMID:33164752]
6. Hanaoka K, Qian F, Boletta A, Bhunia AK, Piontek K, Tsiokas L, Sukhatme VP, Guggino WB, Germino GG. (2000) Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature, 408 (6815): 990-4. [PMID:11140688]
7. Koulen P, Cai Y, Geng L, Maeda Y, Nishimura S, Witzgall R, Ehrlich BE, Somlo S. (2002) Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol, 4 (3): 191-7. [PMID:11854751]
8. Li Q, Dai Y, Guo L, Liu Y, Hao C, Wu G, Basora N, Michalak M, Chen XZ. (2003) Polycystin-2 associates with tropomyosin-1, an actin microfilament component. J Mol Biol, 325 (5): 949-62. [PMID:12527301]
9. Li Q, Montalbetti N, Shen PY, Dai XQ, Cheeseman CI, Karpinski E, Wu G, Cantiello HF, Chen XZ. (2005) Alpha-actinin associates with polycystin-2 and regulates its channel activity. Hum Mol Genet, 14 (12): 1587-603. [PMID:15843396]
10. Li Q, Shen PY, Wu G, Chen XZ. (2003) Polycystin-2 interacts with troponin I, an angiogenesis inhibitor. Biochemistry, 42 (2): 450-7. [PMID:12525172]
11. Li X, Luo Y, Starremans PG, McNamara CA, Pei Y, Zhou J. (2005) Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat Cell Biol, 7 (12): 1202-12. [PMID:16311606]
12. Li Y, Wright JM, Qian F, Germino GG, Guggino WB. (2005) Polycystin 2 interacts with type I inositol 1,4,5-trisphosphate receptor to modulate intracellular Ca2+ signaling. J Biol Chem, 280 (50): 41298-306. [PMID:16223735]
13. Liu X, Vien T, Duan J, Sheu SH, DeCaen PG, Clapham DE. (2018) Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. Elife, 7. [PMID:29443690]
14. Luo Y, Vassilev PM, Li X, Kawanabe Y, Zhou J. (2003) Native polycystin 2 functions as a plasma membrane Ca2+-permeable cation channel in renal epithelia. Mol Cell Biol, 23 (7): 2600-7. [PMID:12640140]
15. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A et al.. (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science, 272 (5266): 1339-42. [PMID:8650545]
16. Obermüller N, Gallagher AR, Cai Y, Gassler N, Gretz N, Somlo S, Witzgall R. (1999) The rat pkd2 protein assumes distinct subcellular distributions in different organs. Am J Physiol, 277 (6): F914-25. [PMID:10600939]
17. Pei Y, Wang K, Kasenda M, Paterson AD, Liang Y, Huang E, Lian J, Rogovea E, Somlo S, St George-Hyslop P. (1998) A novel frameshift mutation induced by an adenosine insertion in the polycystic kidney disease 2 (PKD2) gene. Kidney Int, 53 (5): 1127-32. [PMID:9573526]
18. Pei Y, Watnick T, He N, Wang K, Liang Y, Parfrey P, Germino G, St George-Hyslop P. (1999) Somatic PKD2 mutations in individual kidney and liver cysts support a "two-hit" model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol, 10 (7): 1524-9. [PMID:10405208]
19. Pelucchi B, Aguiari G, Pignatelli A, Manzati E, Witzgall R, Del Senno L, Belluzzi O. (2006) Nonspecific cation current associated with native polycystin-2 in HEK-293 cells. J Am Soc Nephrol, 17 (2): 388-97. [PMID:16396967]
20. Pennekamp P, Bogdanova N, Wilda M, Markoff A, Hameister H, Horst J, Dworniczak B. (1998) Characterization of the murine polycystic kidney disease (Pkd2) gene. Mamm Genome, 9 (9): 749-52. [PMID:9716661]
21. Qian F, Germino FJ, Cai Y, Zhang X, Somlo S, Germino GG. (1997) PKD1 interacts with PKD2 through a probable coiled-coil domain. Nat Genet, 16 (2): 179-83. [PMID:9171830]
22. Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Somlo S, Harris PC, Torres VE, Sieck GC. (2003) Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum Mol Genet, 12 (15): 1875-80. [PMID:12874107]
23. Reynolds DM, Hayashi T, Cai Y, Veldhuisen B, Watnick TJ, Lens XM, Mochizuki T, Qian F, Maeda Y, Li L et al.. (1999) Aberrant splicing in the PKD2 gene as a cause of polycystic kidney disease. J Am Soc Nephrol, 10 (11): 2342-51. [PMID:10541293]
24. Rundle DR, Gorbsky G, Tsiokas L. (2004) PKD2 interacts and co-localizes with mDia1 to mitotic spindles of dividing cells: role of mDia1 IN PKD2 localization to mitotic spindles. J Biol Chem, 279 (28): 29728-39. [PMID:15123714]
25. Tsiokas L, Arnould T, Zhu C, Kim E, Walz G, Sukhatme VP. (1999) Specific association of the gene product of PKD2 with the TRPC1 channel. Proc Natl Acad Sci USA, 96 (7): 3934-9. [PMID:10097141]
26. Tsiokas L, Kim E, Arnould T, Sukhatme VP, Walz G. (1997) Homo- and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc Natl Acad Sci USA, 94 (13): 6965-70. [PMID:9192675]
27. Viribay M, Hayashi T, Tellería D, Mochizuki T, Reynolds DM, Alonso R, Lens XM, Moreno F, Harris PC, Somlo S et al.. (1997) Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene. Hum Genet, 101 (2): 229-34. [PMID:9402976]
28. Wang Z, Ng C, Liu X, Wang Y, Li B, Kashyap P, Chaudhry HA, Castro A, Kalontar EM, Ilyayev L et al.. (2019) The ion channel function of polycystin-1 in the polycystin-1/polycystin-2 complex. EMBO Rep, 20 (11): e48336. [PMID:31441214]
29. Wu G, D'Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou Jr H, Kucherlapati R et al.. (1998) Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell, 93 (2): 177-88. [PMID:9568711]
30. Wu G, Markowitz GS, Li L, D'Agati VD, Factor SM, Geng L, Tibara S, Tuchman J, Cai Y, Park JH et al.. (2000) Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat Genet, 24 (1): 75-8. [PMID:10615132]
31. Wu G, Mochizuki T, Le TC, Cai Y, Hayashi T, Reynolds DM, Somlo S. (1997) Molecular cloning, cDNA sequence analysis, and chromosomal localization of mouse Pkd2. Genomics, 45 (1): 220-3. [PMID:9339380]
32. Wu G, Tian X, Nishimura S, Markowitz GS, D'Agati V, Park JH, Yao L, Li L, Geng L, Zhao H et al.. (2002) Trans-heterozygous Pkd1 and Pkd2 mutations modify expression of polycystic kidney disease. Hum Mol Genet, 11 (16): 1845-54. [PMID:12140187]
33. Xenophontos S, Constantinides R, Hayashi T, Mochizuki T, Somlo S, Pierides A, Deltas CC. (1997) A translation frameshift mutation induced by a cytosine insertion in the polycystic kidney disease 2 gene (PDK2). Hum Mol Genet, 6 (6): 949-52. [PMID:9175744]
