Taking a translational turn

This month's installment of Generally Physiological takes a translational turn, discussing functional analyses of two proteins whose mutation is associated with disease (heart failure and cystic fibrosis, respectively) and the mechanism underlying the painful response to cold found in ciguatera. A tunable brake on cardiac contractility Cardiac contraction, like that of skeletal muscle, depends on the interaction of myosin thick filaments with actin thin filaments, which slide past each other to shorten the sar-comeres that make up muscle fibers. Although mutations in cardiac myosin–binding protein C (cMyBP-C, which binds to thick filaments) have been linked to heart disease, its precise physiological role—and thus the mechanisms underlying the pathophysiological consequences of its malfunction—has been unclear (see Burghardt and Ajtai, 2012). Previs et al. (2012) developed an in vitro sarcomere model in which they visualized the movement of fluorescently labeled actin filaments along thick filaments immobilized on coverslips. Analyses of actin movement along thick filaments isolated from the hearts of wild-type mice or mice lacking cMyBP-C revealed that cMyBP-C, which localizes to a particular region of the thick filament (the C-zone), acts in this region to slow actin movement. -adrenergic stimulation of the heart promotes cMyBP-C phosphorylation, and manipulation of the degree of phos-phorylation revealed that increasing phosphorylation of cMyBP-C was associated with a graded reduction in its inhibition of actin filament velocity. Thus, the authors propose that cMyBP-C enables the fine-tuning of cardiac contraction, providing a potential mechanism to link its loss or dysfunction to aberrant cardiac contractility. The cystic fibrosis transmembrane reporter (CFTR, mutation of which leads to cystic fibrosis) is unusual in being an ATP-gated chloride channel in a family of active transporters (the ATP-binding cassette [ABC] protein superfamily). Unlike active transporters, which couple ATP hydrolysis to substrate movement against a concentration gradient, channels mediate the passive trans-membrane diffusion of ions down their concentration gradients. Thus, there is no clear requirement for the energy derived from ATP hydrolysis in CFTR function (see Tsai, 2012). Noting that CFTR retains key structural elements common to other members of the ABC family, Jih et al. (2012) exploited a mutant form of the CFTR that exhibits two different open states (characterized by distinct conductances) to explore the role of ATP hydrolysis by CFTR. They found that ATP hydrolysis promoted transition between these two open states in a preferred order, indicating that CFTR gating involves an irreversible step that requires input of energy, so …