Ancestral TSH mechanism signals summer in a photoperiodic mammal

SummaryIn mammals, day-length-sensitive (photoperiodic) seasonal breeding cycles depend on the pineal hormone melatonin, which modulates secretion of reproductive hormones by the anterior pituitary gland [1]. It is thought that melatonin acts in the hypothalamus to control reproduction through the release of neurosecretory signals into the pituitary portal blood supply, where they act on pituitary endocrine cells [2]. Contrastingly, we show here that during the reproductive response of Soay sheep exposed to summer day lengths, the reverse applies: Melatonin acts directly on anterior-pituitary cells, and these then relay the photoperiodic message back into the hypothalamus to control neuroendocrine output. The switch to long days causes melatonin-responsive cells in the pars tuberalis (PT) of the anterior pituitary to increase production of thyrotrophin (TSH). This acts locally on TSH-receptor-expressing cells in the adjacent mediobasal hypothalamus, leading to increased expression of type II thyroid hormone deiodinase (DIO2). DIO2 initiates the summer response by increasing hypothalamic tri-iodothyronine (T3) levels. These data and recent findings in quail [3] indicate that the TSH-expressing cells of the PT play an ancestral role in seasonal reproductive control in vertebrates. In mammals this provides the missing link between the pineal melatonin signal and thyroid-dependent seasonal biology

Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells

We investigated the contribution of the intracellular calcium (Cai2+) transient to acetylcholine (ACh)-mediated reduction of pacemaker frequency and cAMP content in rabbit sinoatrial nodal (SAN) cells. Action potentials (whole cell perforated patch clamp) and Cai2+ transients (Indo-1 fluorescence) were recorded from single isolated rabbit SAN cells, whereas intracellular cAMP content was measured in SAN cell suspensions using a cAMP assay (LANCE®). Our data show that the Cai2+ transient, like the hyperpolarization-activated “funny current” (If) and the ACh-sensitive potassium current (IK,ACh), is an important determinant of ACh-mediated pacemaker slowing. When If and IK,ACh were both inhibited, by cesium (2 mM) and tertiapin (100 nM), respectively, 1 μM ACh was still able to reduce pacemaker frequency by 72%. In these If and IK,ACh-inhibited SAN cells, good correlations were found between the ACh-mediated change in interbeat interval and the ACh-mediated change in Cai2+ transient decay (r2 = 0.98) and slow diastolic Cai2+ rise (r2 = 0.73). Inhibition of the Cai2+ transient by ryanodine (3 μM) or BAPTA-AM (5 μM) facilitated ACh-mediated pacemaker slowing. Furthermore, ACh depressed the Cai2+ transient and reduced the sarcoplasmic reticulum (SR) Ca2+ content, all in a concentration-dependent fashion. At 1 μM ACh, the spontaneous activity and Cai2+ transient were abolished, but completely recovered when cAMP production was stimulated by forskolin (10 μM) and IK,ACh was inhibited by tertiapin (100 nM). Also, inhibition of the Cai2+ transient by ryanodine (3 μM) or BAPTA-AM (25 μM) exaggerated the ACh-mediated inhibition of cAMP content, indicating that Cai2+ affects cAMP production in SAN cells. In conclusion, muscarinic receptor stimulation inhibits the Cai2+ transient via a cAMP-dependent signaling pathway. Inhibition of the Cai2+ transient contributes to pacemaker slowing and inhibits Cai2+-stimulated cAMP production. Thus, we provide functional evidence for the contribution of the Cai2+ transient to ACh-induced inhibition of pacemaker activity and cAMP content in rabbit SAN cells

La mélatonine dans le système circadien

Chez les Mammifères l'horloge biologique circadienne principale est localisée dans les noyaux suprachiasmatiques de l'hypothalamus. Cette horloge, dont la période est légèrement différente de 24 heures, est synchronisée avec le temps astronomique, essentiellement par le cycle jour/nuit. Pour cette remise à l'heure, les différents synchroniseurs agissent sur la boucle moléculaire principale à la base des oscillations circadiennes et plus particulièrement sur les gènes Per1 et Per2 . Une fois construites et synchronisées, les oscillations circadiennes sont distribuées à tout l'organisme par des signaux efférents de l'horloge, et l'interaction complexe entre les signaux nerveux, endocrines et/ou comportementaux permet l'organisation temporelle des fonctions. La mélatonine est un important signal hormonal efférent de l'horloge qui définit la "nuit biologique". Elle est capable d'imposer un rythme circadien aux structures qui expriment des récepteurs de la mélatonine, et joue un rôle majeur dans l'homéostasie temporelle. La présence de récepteurs de la mélatonine dans les noyaux suprachiasmatiques indique que l'hormone rétro-agit sur l'horloge elle-même et donc, que la mélatonine exogène a la capacité d'agir sur le système circadien, ce qui a été démontré expérimentalement (effet chronobiotique). La mélatonine peut donc agir comme un synchroniseur de l'horloge. Par contre, et de façon surprenante car contraire à celui des autres synchroniseurs, cet effet chronobiotique de la mélatonine ne passe pas par une action directe sur les gènes Per1 et/ou Per2, mais sur Rev-erb α, un gène impliqué dans la boucle modulatrice de la machinerie moléculaire de l'horloge

MT1 melatonin receptor mRNA expressing cells in the pars tuberalis of the european hamster: Effect of photoperiod

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