In rodents, norepinephrine (NE) is released nocturnally from the intrapineal nerve endings of sympathetic neurons originating from the superior cervical ganglion (21) and binds to a- and P -adrenergic receptors on the pinealocyte membrane (32). The - and -adrenergic receptors are the predominant neurotransmitter receptors in the rodent pineal organ. Of all rat tissues tested the pineal organ exerts the highest expression of 1-adrenergic receptor mRNA (40). Beside these adrenergic receptors, which are in the focus of this contribution, many other, e.g. peptidergic-, monoaminergic-, and cholinergic receptors are present in the rodent pineal gland as well (61,39). However, the P 1 -adrenergic receptor appears to be most important for AANAT mRNA upregu-lation and stimulation of melatonin biosynthesis (32,61,35).
The transcription of the P 1-adrenergic receptor (Pb-ADR) is developmentally regulated, fluctuates diurnally and is gated by a CAMP-dependent mechanism in rodent pinealocytes (see 14,46,51). P rADR mRNA levels are low during the light phase and start to increase immediately after the onset of darkness (Figure 1).The maximum level is reached in the middle of the dark period and falls thereafter. This rhythm
Figure 1. P1- ADR mRNA is regulated in a diurnal and circadian manner. The Pi -ADR mRNA level (in O.D.) is low during the light phase and starts to increase immediately after onset of darkness (open squares). The maximum is reached in the middle of the dark period and falls thereafter. This rhythm persists in constant darkness (black circles), but is ablated in ganglionectomized animals (open circles).
persists in constant darkness, is ablated in ganglionectomized animals and is therefore truly circadian (51; Figure 1). Interestingly the expression of the a 1 B-adrenergic receptor is regulated in a very similar way (19) and both the a- and the P-adrenergic receptors can be modulated posttranscriptionally (17). P1-ADR transcription is not directly correlated with receptor abundancy, since the rhythmic fluctuation in ligand binding sites in the rat pineal gland reaches elevated levels at the earliest 7 h after the nocturnal peak in P 1 -ADR mRNA levels (52,51). From this time lag, it can be reasoned that the receptor protein rests in a sequestered state and that its incorporation into the pinealocyte membranes is suspended until the lack of ligand during daytime triggers this event. For the P 2-ADR it has been demonstrated that continuous exposure to agonists leads to a homologous receptor desensitization within minutes. This event is followed by a receptor down regulation which is maintained for hours on a steady-state receptor level by a cyclic AMP-dependent lowering of receptor transcription (17). However, these classical ligand-dependent regulations, common for many other G-protein coupled receptors, apply for pineal P 1-ADR fluctuations only to a limited extent: rhythms in P 1-ADR mRNA and protein are notably out of frame and driven either by the presence ( 1-ADR mRNA) or the absence (P-ADR protein) of the ligand (51). The findings suggest that the rhythm in biochemical activities of the rat pineal gland, which is induced by the nocturnally elevated release of NE, seems to be stabilized in two ways already at the P 1-ADR level: NE-induced P 1 -ADR transcription provides the basis to react to daytime ligand depriviation with an upregulation in receptor abundancy. At the same time NE rapidly sequesters ligand binding sites in the rat pineal gland as a protective mechanism, diminishing CAMP-mediated physiological responses despite the presence of a constant NE stimulus. The constantly elevated level in P 1-ADR mRNA in the pineal gland of SCGX animals can be explained by the the absence of a protective function provided by the sympathetic nerve endings against circulating catecholamines (49). Similarly, the amount of P 1-ADR mRNA in the rat pineal gland is elevated until postnatal day 8 and is not yet regulated. It is only when the sympathetic innervation of the pineal gland gains function at the beginning of the second postnatal week (66,33) that P1-ADR mRNA levels decrease during daytime and become rhythmic. Interestingly, this developmental pattern in P 1-ADR mRNA closely matches the dynamics in adrenergic binding sites (4) and is similar to the ontogeny of pineal NAT activity rhythm (33,22). Thus, the maturation in NE/P1-ADR interaction (4) coincides with a complete maturation of the cyclic AMP signaling pathway (22,33,61,64).
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