Posts Tagged: human

Genetics and Genomics of Congenital Heart Disease

Genetics and Genomics of Congenital Heart Disease

Samir Zaidi, Martina Brueckner

NOTCH signaling in congenital heart disease (CHD) (A) the outline of NOTCH signaling pathway showing signal-sending cell in yellow and signal receiving cell in green. B, Syndromes and CHD associated with NOTCH pathway gene mutations. BAV indicates bicuspid aortic valve; CoA, coarctation of the aorta; HLHS, hypoplastic left heart syndrome; HTX, heterotaxy-associated defects; NA, not applicable; NICD, Notch intracellular domain; VSD, ventricular septal defect; TA, truncus arteriosus; and TOF, tetralogy of Fallot. [Powerpoint File]

Genetics and Genomics of Congenital Heart Disease

Genetics and Genomics of Congenital Heart Disease

Samir Zaidi, Martina Brueckner

A, Outline of human heart development. The x axis displays days of human and mouse gestation. B, The spectrum of congenital heart disease from mild to severe. The lesions indicated as “severe” are expected to require intervention in the first year of life. Classes of CHD based on proposed developmental-genetic mechanisms are indicated in parentheses. C, Genetic causes of CHD identified to date. ASD indicates atrial septal defect; CHD, congenital heart disease; CoA, coarctation of the aorta; CTD, conotruncal defect; HLHS, hypoplastic left heart syndrome; HTX, heterotaxy; LVO, left ventricular outflow obstruction; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; and VSD, ventricular septal defect. [Powerpoint File]

Control of Cardiac Repolarization by Phosphoinositide 3-Kinase Signaling to Ion Channels

Control of Cardiac Repolarization by Phosphoinositide 3-Kinase Signaling to Ion Channels

Lisa M. Ballou, Richard Z. Lin, Ira S. Cohen

Phosphoinositide 3-kinase (PI3K) signaling pathways regulating cardiac ion channels. Receptor tyrosine kinases (RTKs) such as the insulin receptor activate PI3Kα to produce phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3), which recruits Akt and 3-phosphoinositide-dependent protein kinase 1 (PDK1) to the plasma membrane, resulting in Akt activation. RTKs can also activate atypical PKCs (aPKC) and serum- and glucocorticoid-regulated kinase (SGK) via PDK1. Gβγ subunits released from G-protein–coupled receptors (GPCRs) activate PI3Kγ to increase PI(3,4,5)P3 production and activate Akt, but the Gαq subunits inhibit PI3Kα. Akt, PDK1, aPKC, SGK, and possibly other downstream effectors of PI3K regulate ion channels that conduct potassium, sodium, and calcium currents. Phosphatase and tensin homolog (PTEN) dephosphorylates PI(3,4,5)P3 to antagonize PI3K signaling. PI3Kγ also binds to and activates phosphodiesterases (PDE) to decrease cAMP, a second messenger that regulates many cardiac ion channels. This function of PI3Kγ is independent of its kinase activity. ICa,L indicates L-type calcium current; IKr, rapid delayed rectifier current; IKs, slow delayed rectifier current; and INa, sodium current. [Powerpoint File]