PERIOD proteins are central components of the Drosophila and mammalian circadian clock. Their function is controlled by daily changes in synthesis, cellular localization, phosphorylation, degradation, as well as specific interactions with other clock components. Here we present the crystal structure of a Drosophila PERIOD (dPER) fragment comprising two tandemly organized PAS (PER-ARNT-SIM) domains (PAS-A and PAS-B) and two additional C-terminal alpha helices (alphaE and alphaF). Our analysis reveals a noncrystallographic dPER dimer mediated by intermolecular interactions of PAS-A with PAS-B and helix alphaF. We show that alphaF is essential for dPER homodimerization and that the PAS-A-alphaF interaction plays a crucial role in dPER clock function, as it is affected by the 29 hr long-period perL mutation.
Environmental cues modulate a variety of intracellular pathways whose signaling is integrated by the molecular mechanism that constitutes the circadian clock. Although the essential gears of the circadian machinery have been elucidated, very little is known about the signaling systems regulating it. Here, we report that signaling mediated by the dopamine D2 receptor (D2R) enhances the transcriptional capacity of the CLOCK:BMAL1 complex. This effect involves the mitogen-activated protein kinase transduction cascade and is associated with a D2R-induced increase in the recruiting and phosphorylation of the transcriptional coactivator cAMP-responsive element-binding protein (CREB) binding protein. Importantly, CLOCK:BMAL1-dependent activation and light-inducibility of mPer1 gene transcription is drastically dampened in retinas of D2R-null mice. Because dopamine is the major catecholamine in the retina, central for the neural adaptation to light, our findings establish a physiological link among photic input, dopamine signaling, and the molecular clock machinery.circadian clock ͉ dopamine receptors ͉ light ͉ retina
Abstract-Release of norepinephrine (NE) by the hypothalamic nuclei may contribute to regulation of sympathetic nervous system (SNS) activity. Angiotensin-(1-7) [Ang-(1-7)] has an antihypertensive effect and may decrease SNS activity. We tested the hypothesis that Ang-(1-7) inhibits the release of NE in hypothalami, via the Ang-(1-7) and angiotensin II type 2 (AT 2 ) receptors, acting through a bradykinin (BK)/NO-dependent mechanism. Hypothalami from normotensive controls and spontaneously hypertensive rats (SHR) were isolated and endogenous NE stores labeled by incubating the tissues with [ 3 H]NE. [ 3 H]NE release from the hypothalami was stimulated by KCl in the presence or absence of Ang-(1-7) alone or combined with various antagonists and inhibitors. Ang-(1-7) significantly attenuated K ϩ -induced NE release by hypothalami from normotensive rats but was more potent in SHR. The Ang-(1-7) receptor antagonist ]Ang-(1-7), the AT 2 receptor antagonist PD 123319, and the BK B 2 receptor antagonist icatibant all blocked the inhibitory effect of Ang-(1-7) on K ϩ -stimulated NE release in SHR. The inhibitory effect of Ang-(1-7) disappeared in the presence of the NO synthase inhibitor N G -nitro-L-arginine methyl ester and was restored by the precursor of NO, L-arginine. The diminished NE release caused by Ang-(1-7) was blocked by a soluble guanylyl cyclase inhibitor as well as by a cGMP-dependent protein kinase (PKG). We concluded that Ang-(1-7) decreases NE release from the hypothalamus via the Ang-(1-7) or AT 2 receptors, acting through a BK/NO-mediated mechanism that stimulates cGMP/PKG signaling. In this way, Ang-(1-7) may decrease SNS activity and exert an antihypertensive effect. ] has been shown to be the most pleiotropic bioactive component of the renin-angiotensin system because it exerts effects that may be identical to, different from, or opposite from those displayed by angiotensin II (Ang II). 1 For instance, it lacks the vasoconstrictor aldosterone secretagogue or dipsogenic effects of Ang II. 1,2 However, it mimics Ang II stimulation of vasopressin and prostaglandin release 1 as well as peripheral norepinephrine (NE) outflow. 3 In contrast, Ang-(1-7) causes natriuresis, diuresis, and vasodilatation and inhibits angiogenesis and cellular growth, 1,2 suggesting that in many cases, this peptide may act as an endogenous antagonist of Ang II. In fact, Ang-(1-7) has been suggested as having an antihypertensive effect as well as counterbalancing the pressor and proliferative actions of Ang II because some of its effects that oppose those of Ang II are enhanced in rat models of hypertension. 1,4 It has been demonstrated that the Mas proto-oncogene, originally considered to be an "orphan" G-protein-coupled receptor involved in phospholipase C activation, 5 binds Ang-(1-7) and is involved in the biological actions of this heptapeptide. 6 Genetic deletion of the Mas receptor abolishes not only binding of Ang-(1-7) to mouse kidneys but also Ang-(1-7)-induced relaxation and antidiuretic responses, suggesting that ...
Disruption of overt circadian rhythms can occur without influencing the endogenous pacemaker, the so-called 'masking' effect classically elicited by light. As the physiological pathways involved in light masking remain elusive, we analyzed mice lacking the dopamine D2 receptor. Although circadian rhythmicity was normal, D2R-null mice showed a markedly deficient light masking response, indicating that D2R-mediated signaling is an essential component of the neuronal pathways leading to light masking of circadian rhythms.
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