K(ATP) channel gain-of-function leads to increased myocardial L-type Ca(2+) current and contractility in Cantu syndrome.
Proc Natl Acad Sci U S A
; 113(24): 6773-8, 2016 06 14.
Article
em En
| MEDLINE
| ID: mdl-27247394
ABSTRACT
Cantu syndrome (CS) is caused by gain-of-function (GOF) mutations in genes encoding pore-forming (Kir6.1, KCNJ8) and accessory (SUR2, ABCC9) KATP channel subunits. We show that patients with CS, as well as mice with constitutive (cGOF) or tamoxifen-induced (icGOF) cardiac-specific Kir6.1 GOF subunit expression, have enlarged hearts, with increased ejection fraction and increased contractility. Whole-cell voltage-clamp recordings from cGOF or icGOF ventricular myocytes (VM) show increased basal L-type Ca(2+) current (LTCC), comparable to that seen in WT VM treated with isoproterenol. Mice with vascular-specific expression (vGOF) show left ventricular dilation as well as less-markedly increased LTCC. Increased LTCC in KATP GOF models is paralleled by changes in phosphorylation of the pore-forming α1 subunit of the cardiac voltage-gated calcium channel Cav1.2 at Ser1928, suggesting enhanced protein kinase activity as a potential link between increased KATP current and CS cardiac pathophysiology.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Osteocondrodisplasias
/
Cardiomegalia
/
Canais de Cálcio Tipo L
/
Miócitos Cardíacos
/
Canais KATP
/
Receptores de Sulfonilureias
/
Ventrículos do Coração
/
Hipertricose
/
Contração Miocárdica
Limite:
Animals
/
Female
/
Humans
/
Male
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article