The Role of PINA in Copper Transport, Circadian Rhythms, and Wilson’s Disease

Abstract

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 melatonin, 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.