G-Protein coupled receptors: structure and function in drug discovery.

The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into families or classes thus making it one of the largest in the mammalian genome. GPCRs take part in many vital physiological functions making them targets for numerous novel drugs. GPCRs share some distinctive features, such as the seven transmembrane domains, they also differ in the number of conserved residues in their transmembrane domain. Here we provide an introductory and accessible review detailing the computational advances in GPCR pharmacology and drug discovery. An overview is provided on family A-C GPCRs; their structural differences, GPCR signalling, allosteric binding and cooperativity. The dielectric constant (relative permittivity) of proteins is also discussed in the context of site-specific environmental effects.

Congenital heart disease and pregnancy.

Patients with congenital heart disease who wish to become pregnant offer a challenge to obstetricians, cardiologists and anesthetists. Although no large randomized trials exist to support the management of this emerging population, small prospective and retrospective studies provide valuable data on the likely success of pregnancy and the risks involved. Recently, there is emerging consensus on the management of this specialized group of patients, and this article aims to provide the practitioner with an overview of patient needs and the issues to be addressed. All patients with congenital heart disease wishing to consider pregnancy should be referred for specialist assessment prior to conception. Maternal risk, fetal risk and recurrence risk in the fetus should all be addressed. Most women with congenital heart disease can undergo pregnancy without significant risk. However, for some women the risk of maternal death is high, including those with: severe aortic stenosis, impaired left ventricular function, pulmonary hypertension and Marfan syndrome with dilated aortic root. All patients should be offered a detailed 20-week fetal cardiac scan and, in certain cases, prepregnancy genetic counseling. Most patients can deliver vaginally, with cesarean section reserved for obstetric indications or patients in whom straining at delivery could be potentially fatal (i.e., those with Marfan syndrome, aortic aneurysm, severe fixed left heart obstruction, or the acutely unwell mother). Antibiotic prophylaxis should be given routinely in labor to all patients in whom dental prophylaxis is indicated.

Cardiac neuronal nitric oxide synthase isoform regulates myocardial contraction and calcium handling.

A neuronal isoform of nitric oxide synthase (nNOS) has recently been located to the cardiac sarcoplasmic reticulum (SR). Subcellular localization of a constitutive NOS in the proximity of an activating source of Ca2+ suggests that cardiac nNOS-derived NO may regulate contraction by exerting a highly specific and localized action on ion channels/transporters involved in Ca2+ cycling. To test this hypothesis, we have investigated myocardial Ca2+ handling and contractility in nNOS knockout mice (nNOS-/-) and in control mice (C) after acute nNOS inhibition with 100 micromol/L L-VNIO. nNOS gene disruption or L-VNIO increased basal contraction both in left ventricular (LV) myocytes (steady-state cell shortening 10.3+/-0.6% in nNOS-/- versus 8.1+/-0.5% in C; P<0.05) and in vivo (LV ejection fraction 53.5+/-2.7 in nNOS-/- versus 44.9+/-1.5% in C; P<0.05). nNOS disruption increased ICa density (in pA/pF, at 0 mV, -11.4+/-0.5 in nNOS-/- versus -9.1+/-0.5 in C; P<0.05) and prolonged the slow time constant of inactivation of ICa by 38% (P<0.05), leading to an increased Ca2+ influx and a greater SR load in nNOS-/- myocytes (in pC/pF, 0.78+/-0.04 in nNOS-/- versus 0.64+/-0.03 in C; P<0.05). Consistent with these data, [Ca2+]i transient (indo-1) peak amplitude was greater in nNOS-/- myocytes (410/495 ratio 0.34+/-0.01 in nNOS-/- versus 0.31+/-0.01 in C; P<0.05). These findings have uncovered a novel mechanism by which intracellular Ca2+ is regulated in LV myocytes and indicate that nNOS is an important determinant of basal contractility in the mammalian myocardium. The full text of this article is available at http://www.circresaha.org.