Functional role of TASK-1 in the heart: studies in TASK-1-deficient mice show prolonged cardiac repolarization and reduced heart rate variability.

TASK-1, a member of the recently identified K2P channel family, is mainly expressed in the heart and the nervous system. TASK-1 is regulated by several physiological and pathological conditions and functions as a background potassium channel. However, there are limited data concerning the significance of TASK-1 in cardiac physiology. We studied the functional role of TASK-1 in the heart by cardiac phenotyping the TASK-1-deficient mouse (TASK-1(-/-)). TASK-1 was predominantly expressed in the ventricles of control animals. Real-time PCR and immunoblot demonstrated that the expression of seven other K2P channels was unchanged in TASK-1(-/-) mice. No structural or functional abnormalities were found by histology and echocardiography. Electrophysiological studies recording monophasic action potentials (MAPs) showed a significant prolongation of action potential duration in spontaneously beating and atrially paced hearts, respectively. Surface ECGs of TASK-1(-/-) mice revealed a significant prolongation of the rate corrected QT interval. Telemetric ECG recordings for 24 h, during physical and pharmacological stress testing and after ischemia/reperfusion injury did not result in a higher incidence of arrhythmias. Infarct size was comparable in both genotypes. However, TASK-1(-/-) mice had a higher mean heart rate and significantly reduced heart rate variability (HRV). Time and frequency domain measurements as well as baroreceptor reflex testing revealed a sympathovagal imbalance with a shift to an increase in sympathetic influence in TASK-1(-/-) mice. In conclusion, TASK-1 plays a functional role in the repolarization of the cardiac action potential in vivo and contributes to the maintenance of HRV.

The GABA(A) receptor complex in the chicken brain: immunocytochemical distribution of alpha 1- and gamma 2-subunits and autoradiographic distribution of BZ1 and BZ2 binding sites.

Two antibodies, raised against the rat GABA(A) receptor alpha1- and gamma2-subunits, were used for an immunocytochemical study of the distribution of these proteins in the chicken brain. The immunoreactive bands obtained by Western blotting and the similar labelling distribution found in the rat and chicken brain support the suitability of these antibodies for the labelling of GABA(A) receptors in birds. We found abundant alpha1 and gamma2 immunoreactivity throughout the chicken brain, mainly in the paleostriata and lobus paraolfactorius, dorsal thalamus and some nuclei of the brainstem. The alpha1-subunit was more abundant in the telencephalon, thalamus and cerebellum, while the presence of the gamma2-subunit was stronger in the optic tectum and brainstem. We also report the autoradiographic distribution of the BZ1 and BZ2 benzodiazepine receptor subtypes in the chicken brain using [3H]flunitrazepam. Benzodiazepine binding was unevenly distributed throughout the chicken brain, and the anatomical distribution of the BZ1 and BZ2 subtypes was similar to that described in mammals. The highest binding values were found in the olfactory bulb, paleostriatum primitivum, optic tectum, nucleus mesencephalicus lateralis pars dorsalis and nucleus isthmi pars parvocellularis, the BZ2 subtype being predominant in the paleostriatum primitivum and optic tectum. A general agreement in the distribution of BZ1 and alpha1 immunoreactivity was observed in structures such as the olfactory bulb, paleostriata, lobus parolfactorius and dorsal thalamus, although some discrepancies were observed in areas such as the optic tectum or nucleus isthmi pars parvocellularis, with high BZ1 binding and low or no alpha1 immunolabelling.