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Thyroid hormone–dependent regulation of ZAKI-4&agr;, an inhibitor of calcineurin, and its implication in brain development and function

Calcineurin (Cn) is a serine/threonine protein phosphatase activated by Ca2+/calmodulin signaling. It plays crucial roles in synaptic plasticity, memory, and neuronal cell death. Thyroid hormone also plays an important role in the development and maturation of the central nervous system, affecting the pathway regulated by Cn. The purpose of this review is to present evidence and to speculate that modulation of Cn activity by thyroid hormone plays a role in regulating the function of the central nervous system. It is demonstrated that ZAKI-4&agr; is an endogenous inhibitor of Cn and is upregulated by thyroid hormone in human skin fibroblasts. The increase in ZAKI-4&agr; is associated with a decrease in endogenous Cn activity. ZAKI-4&agr; is expressed predominantly in human and rat brains. Its expression overlaps with that of Cn in some brain areas, such as cerebral cortex, hippocampus, and cerebellum. Furthermore, ZAKI-4&agr; expression in some areas of rat brain is regulated by thyroid hormone. Thyroid hormone plays important roles in brain development and maturation. The predominant expression of ZAKI-4&agr; in brain and thyroid hormone–dependent regulation of Cn activity provides new insight into the understanding of brain development and maturation through complex signaling from thyroid hormone to Ca2+-mediated Cn signaling.