Rapid Signaling Pathway for Corticosteriods

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IBN-9604200 Orchinik Steroid hormones are among the most powerful regulators of brain function and behavior known. For this reason, understanding the mechanism for steroid actions is a fundamental problem for neuroendocrinology and behavioral neuroscience. Until recently, steroids were thought to act through a two-step process. Steroids, such as estradiol, testosterone, and corticosterone, first enter the brain and bind to specific receptors found within target neurons. The steroid-receptor complex is then activated and binds to DNA, which in turn, regulates gene expression and alters protein synthesis. It is the increase or decrease of proteins that bring about the physiological and behavioral response to the steroid hormones. This is referred to as the genomic mechanism of steroid action and the time frame of action requires anywhere from hours to days. A conceptual problem exists since many neural actions of steroid appear and decrement very rapidly. This is especially true for corticosterone, an adrenal steroid, that is released during stress. Indeed, it has been known for years that under stressful conditions, corticosteroids levels rise dramatically within 2-5 minutes, peak within 30 minutes, and return to basal levels almost as quickly with the cessation of the stressful event. Dr. Orchinik believes that under acute stress conditions, corticosteroid is acting through a non-genomic mechanism and this award addresses this important question. He hypothesizes that corticosteroids are eliciting rapid neuronal responses by first binding to receptors in the neuronal membranes rather than within the neuron. Dr. Orchinik will carry out a series of studies that systematically investigate the molecular mechanisms that underlie neurophysiological and behavioral responses to corticosteroid that are too rapid to be accounted for by the genomic mechanism of action. Initial studies will establish and characterized the presence of corticosterone r eceptors in neuronal membranes. The membrane-bound and intracellular corticosteroid brain receptors will then be compared. Using an array of techniques, Dr. Orchinik will then examine the events that occur after corticosterone binds to the membrane receptors. He will determine whether the signal transduction initiated by the membrane-bound steroid involved receptor interactions with GTP binding proteins, similar to the action of neurotransmitters. The results from these studies will identify the biochemical pathways involved in the rapid corticosteroid action. The new knowledge gained from these studies will help us decipher both the genomic and non-genomic mechanisms of steroid action which is essential if we are to understand of how hormones modulate brain function and behavior, in particular, neural responses to stress.