Cortisol is synthesized by adrenal zona fasciculata (AZG) cells and is secreted in a diurnal rhythm under the control of the pituitary peptide ACTH. Superimposed on this basal oscillatory pattern, physical and psychological stress trigger bursts of cortisol production by activating the hypothalamic-pituitary-adrenal axis. Cortisol acts on liver, muscle, and adipose cells to regulate energy balance and to maintain blood glucose at constant levels. Precise control of blood glucose is critical because this sugar acts as the brain s prime energy source; hypoglycemia rapidly leads to brain damage and death. Aberrant cortisol secretion is responsible for significant endocrine pathology including Cushing s and Addison s diseases. Prolonged cortisol secretion as can occur in chronic stress leads to hippocampal damage, accompanied by learning and memory deficits. At the cellular level, the biochemical and electrophysiological mechanisms that regulate ACTHstimulated cortisol production are incompletely understood. However, a pivotal role for specific ion channels and depolarization-dependent calcium entry has been established. In patch clamp studies on bovine AZF cells, we have identified three types of ion channels that together determine the electrical properties of these cells and orchestrate the ionic events involved in cortisol secretion. These studies have led us to hypothesize that ACTH exerts both rapid and delayed control over the electrical and secretory activity of bovine AZF cells by modulating the activity and the expression of genes coding for these ion channels. The studies described in this proposal will be designed to complete a comprehensive description of the regulation of ion channel function and gene expression by ACTH in bovine AZF cells, including the biophysical and molecular mechanisms and signaling pathways that mediate these responses. The ACTH-induced changes in ion channel function and gene expression will be correlated with corresponding rapid and delayed effects on electrical activity and cortisol synthesis. This basic knowledge will be essential to our ultimate goal of understanding AZF cell physiology under normal and pathological conditions. Project Description
PUBLIC HEALTH RELEVANCE Cortisol released from the adrenal cortex acts on liver, muscle, and adipose cells to regulate energy balance and to maintain blood glucose at constant levels. Precise control of blood glucose is critical because this sugar acts as the brain?s prime energy source;hypoglycemia rapidly leads to brain damage and death. Aberrant cortisol secretion is also responsible for significant endocrine pathology including Cushing?s and Addison?s diseases.
