Jimo Borjigin Xing Sun and Michael M Wang

1. INTRODUCTION

Circadian rhythms are found in virtually all organisms and are tightly coupled to environmental lighting conditions. These rhythms dictate our daily sleep schedule and hormonal fluctuations (1) and even influence our susceptibility to disease such as heart attacks (2), strokes (3), and seizures (4). One of the best studied circadian rhythms is the activity of the pineal gland, an organ situated deep within the brain. The pineal exhibits dramatic diurnal fluctuations in secretion of the hormone mela-tonin, which is best known for its soporific effects in humans. Melatonin is the only vertebrate hormone that is known to universally link environmental light information to the body's physiological responses, including clock resetting, seasonal reproduction, and sleep (5). To understand the molecular basis of the circadian regulation of the pineal gland, we identified a set of genes expressed exclusively in the nighttime pineal. One of these genes, the pineal night-specific ATPase (PINA) is the focus of this chapter. PINA is a novel splice form of ATP7B and a putative copper transporter, which is active in the pineal only at night. The identification of PINA suggests that dynamic regulation of copper may play an integral role in circadian rhythms, and the study of PINA's functional differences from ATP7B may prove useful in understanding metal-transporting ATPases.

2. ENZYMATIC SYNTHESIS OF MELATONIN

To understand the role of PINA in circadian biology, one must first review the physiology of the pineal gland. In all animals, the only known function of the pineal is the regulated synthesis of melatonin. Melatonin is synthesized from dietary tryptophan by the actions of four enzymes (Fig. 1). Tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin synthesis, is responsible for the 5' hydroxylation of tryptophan, yielding 5-hydroxytrytophan (5-HTP). A nonspecific aromatic amino acid decarboxylase (AAADC) converts 5-HTP to 5-hydroxytryptamine (5-HT, serotonin). A pineal/retina-specific enzyme serotonin N-acetyltransferase (NAT) acetylates serotonin to form N-acetylserotonin (NAS). Finally, another pineal/retina-specific enzyme, hydroxyindole-O-methyltransferase (HIOMT), catalyzes the conversion of NAS to melatonin.

3. REGULATION OF MELATONIN SYNTHESIS

Melatonin synthesis is ultimately controlled by the suprachiasmatic nucleus (SCN) of the brain, which uses a biological clock and lighting information to rhythmically control neural pathways. One

COOH —n—CH2—CH—NH2 t tryptophan tryptophan hydroxylase (TPH)

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