title: Angiotensin II regulates the activity of mouse suprachiasmatic nuclei neurons.
abstract: Neuropeptide signaling plays key roles in coordinating cellular activity within the suprachiasmatic nuclei (SCN), site of the master circadian oscillator in mammals. The neuropeptide angiotensin II (ANGII) and its cognate receptor AT1, are both expressed by SCN cells, but unlike other SCN neurochemicals, very little is known about the cellular actions of ANGII within this circadian clock. We used multi-electrode, multiunit, extracellular electrophysiology, coupled with whole-cell voltage and current clamp techniques to investigate the actions of ANGII in mouse SCN slices. ANGII (0.001-10 microM) dose dependently stimulated and inhibited extracellularly recorded neuronal discharge in many SCN neurons ( approximately 60%). Both actions were blocked by pre-treatment with the AT1 receptor antagonist ZD7155 (0.03 microM), while suppressions but not activations were prevented by pre-treatment with the GABA A receptor antagonist bicuculline (20 microM). AT1 receptor blockade itself suppressed discharge in a subset ( approximately 30%) of SCN neurons, and this action was not blocked by bicuculline. In voltage-clamped SCN neurons (-70 mV), AT1 receptor activation dose-dependently enhanced the frequency of action potential-driven, GABA A receptor-mediated currents, but did not alter their responses to exogenously applied GABA. In current-clamped SCN neurons perfused with tetrodotoxin, ANGII induced a membrane depolarization with a concomitant decrease in input resistance. In conclusion we show that AT1 receptor activation by ANGII depolarizes SCN neurons and stimulates action potential firing, leading to increased GABA release in the mouse SCN. Additionally we provide the first evidence that endogenous AT1 receptor signaling tonically regulates the activities of some SCN neurons.
authors.affiliation: Faculty of Life Sciences, 1.124 Stopford Building, University of Manchester, Oxford Road, Manchester, UK.
authors.forename: T M
authors.initials: TM
authors.lastname: Brown
authors.forename: E
authors.initials: E
authors.lastname: McLachlan
authors.forename: H D
authors.initials: HD
authors.lastname: Piggins
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005110:Extracellular Space / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011963:Receptors, GABA-A / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D009287:Naphthyridines; D011963:Receptors, GABA-A; C095905:ZD 7155; D000804:Angiotensin II; D005680:gamma-Aminobutyric Acid