Diversity and Plasticity in Binding Sites for Corticosteroids
Miles Orchinik
(co-authors: Creagh Breuner, Paul Gasser, David Jennings)
Department of Biology
Arizona State University
Tempe, AZ
In all vertebrate groups, exposure to a range of stressors produces a transient increase in plasma corticosteroid (CORT) levels. CORT produces a diversity of physiological and behavioral responses following interaction with one or more molecules: plasma corticosteroid binding globulins (CBG), corticosteroid receptors in plasma membranes, and/or intracellular, CORT-activated transcription factors. Comparative studies indicate that many vertebrate species have all these basic types of binding molecules but that there are striking interspecific differences in receptor affinity and/or specificity. For example, the binding specificity of CBG varies greatly between taxa: in rats and many mammals there are distinct corticosteroid-binding and sex hormone-binding globulins, but in the amphibian and reptilian species we have examined, "CBGs" bind androgens with at least as high affinity as they bind corticosterone. This suggests that in nonmammalian vertebrates we may have to consider this inherent plasticity; CORT and "CBG" levels change dynamically but, in addition, corticosteroids and androgens may reciprocally regulate the relative concentrations of bound and free steroids in the plasma. In mammals, there are two major subtypes of intracellular corticoid receptors that regulate gene expression - Type I (mineralocorticoid receptors) with high affinity for CORT and aldosterone and Type II (glucocorticoid receptors) with approximately 10-fold lower affinity for CORT. These receptors are thought to constitute a two-tiered system in brain for responding to basal and stress levels of CORT. However, it is not clear that non-mammalian vertebrates possess intracellular receptor subtypes in the brain with differing affinity for CORT (or aldosterone). This raises questions about the role of brain intracellular receptors in relation to the stress response during vertebrate evolution. Neuronal membrane-associated receptors in vertebrates display a wide range of affinities for corticosterone; the highest affinity receptors appear to be present in species with lowest circulating levels of corticosterone, and the lowest affinity receptors in species with high circulating levels of corticosterone. This suggests that membrane receptors may be best suited for responding to acute changes in corticosteroids during a stress response. Receptors in neuronal membranes appear to mediate "adaptive" behavioral responses to stressors, a critical but largely overlooked component of the organismal response to a threat. All three types of binding sites show plasticity in terms of seasonal and/or behavioral regulation of receptor numbers, and in sensitivity to neuroendocrine environment. In order to understand the adaptive and deleterious actions of corticosteroids, we need to consider the dynamics and plasticity of corticosteroid interaction with plasma, neuronal membrane, and intracellular binding sites for corticosteroids.