A mutation in TRPV4 results in altered chondrocyte calcium signaling in severe metatropic dysplasia

© 2015 Wiley Periodicals, Inc..

Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) is a polymodal modulated non-selective cation channel required for normal development and maintenance of bone and cartilage. Heterozygous mutations of this channel cause a variety of channelopathies, including metatropic dysplasia (MD). We analyzed the effect of a novel TRPV4 mutation c.2398G>A, p.Gly800Asp on intracellular calcium ([Ca(2+) ]i ) regulation in chondrocytes and compared this response to chondrocytes with a frequently observed mutation, c.2396C>T, p.Pro799Leu. We observed temperature-dependent [Ca(2+) ]i oscillations in both intact and MD chondrocytes however, MD mutations exhibited increased peak magnitudes of [Ca(2+) ]i during oscillations. We also found increased baseline [Ca(2+) ]i in MD primary cells, as well as increased [Ca(2+) ]i response to either hypotonic swelling or the TRVP4-specific agonist, GSK1016790A. Oscillations and stimulation responses were blocked with the TRPV4-specific antagonist, GSK205. Analysis of [Ca(2+) ]i response kinetics showed that MD chondrocytes had increased frequency of temperature-sensitive oscillations, and the magnitude and duration of [Ca(2+) ]i responses to given stimuli. Duration of the response of the p.Gly800Asp mutation to stimulation was greater than for the p.Pro799Leu mutation. These experiments show that this region of the channel is essential for proper [Ca(2+) ]i regulation. These studies of primary cells from patients show how both mutant and WT TRPV4 channels regulate cartilage and bone development. © 2015 Wiley Periodicals, Inc.

Medienart:

E-Artikel

Erscheinungsjahr:

2015

Erschienen:

2015

Enthalten in:

Zur Gesamtaufnahme - volume:167A

Enthalten in:

American journal of medical genetics. Part A - 167A(2015), 10 vom: 20. Okt., Seite 2286-93

Sprache:

Englisch

Beteiligte Personen:

Hurd, Lauren [VerfasserIn]
Kirwin, Susan M [VerfasserIn]
Boggs, Mary [VerfasserIn]
Mackenzie, William G [VerfasserIn]
Bober, Michael B [VerfasserIn]
Funanage, Vicky L [VerfasserIn]
Duncan, Randall L [VerfasserIn]

Links:

Volltext

Themen:

Calcium Channel Agonists
Calcium Channel Blockers
Case Reports
Chondrocytes
GMW67QNF9C
Intracellular calcium signaling
Journal Article
Leucine
Metatropic dysplasia
N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Sulfonamides
TRPV Cation Channels
TRPV4
TRPV4 protein, human

Anmerkungen:

Date Completed 14.06.2016

Date Revised 30.09.2020

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1002/ajmg.a.37182

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM251599434