Based on these observations, we concluded that rat pinealocytes are equipped with machineries for input, output and termination of the glutamate signals (Fig. 1). Since the same pinealocytes express all these glutaminergic elements, the glutamate may be used as autocrine- or paracrine-like signals in the endocrine organ: upon stimulation, pinealocytes secrete L-glutamate so as to inhibit NE-stimulated melatonin synthesis. Excess amount of glutamate is rapidly taken up by the reuptake system(s). Thus, melatonin synthesis in pinealocytes is negatively regulated by the glutaminergic systems. The glutamate-evoked regulation of melatonin synthesis seems to be a novel type of hormonal regulation, because a classical neurotransmitter is involved in the hormonal synthesis. Now, we are trying to reveal the elements of the pineal gluta-minergic systems at the molecular level. The glutamate-evoked inhibition of melatonin synthesis is observed even in the presence of NE, indicating that the glutaminergic signal dominates adrenergic control. It is likely that the glutaminergic system functions as an autonomic regulatory mechanism against neuronal control in the pineal gland (Figure 2).
Characterization of the glutaminergic systems shown here causes other important questions to be solved. One is the role of nicotinic acetylcholine receptor (nAchR) in pinealocytes. Recently, we found that acetylcholine triggers glutamate exocytosis via nAchR and inhibits NE-dependent melatonin synthesis through an inhibitory cAMP cascade (33) (Figure 1). Thus, in vivo a stimulant for glutamate exocytosis may be acetylcholine. Our results suggest the very fascinating hypothesis that parasympathetic neurons negatively control melatonin synthesis by way of endogenous glutaminergic systems in pineal glands (Figure 2). We are now performing a series of experiments to test the hypothesis.
Another important question is the role of D-aspartate in pinealocytes. This amino acid was recently found to be present in pinealocytes at extraordinarily high concentration. We found that the D-aspartate is released from pinealocytes by non-vesicular mechanisms other than exocytosis, and it inhibits strongly the NE-stimulated melatonin synthesis (15,17,18). This is the first example for putative physiological functions of the amino acid that its mode of action has been revealed (17,18). The mechanism by which pinealocytes use D-aspartate as a signal transducing molecule may open a new field in pineal physiology.
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