Steven E. Mayer - US grants

The choroid plexus of the brain has several functions, and evidence is accumulating that these are likely to be controlled by drugs, neurotransmitters and hormones. The best known function of the choroid plexus is the secretion of cerebrospinal fluid (CSF) that differs from an ultrafiltrate of plasma. The choroid plexus is innervated, and in recent years it has been shown that both the choroid vasculature and the secretory epithelium are responsive to vasoactive agents and neurohumors. However, little is known about regulatory mechanisms in the epithelium and how they are activated and controlled, because most studies have been conducted in intact animals or in isolated whole choroid plexi that contain blood vessels and other nonepithelial elements. Also, choroid epithelium may display unique pathways of regulation when compared to other secretory epithelia, because the location of ion transport systems on the basal and apical membranes of the cells appear to be the reverse of what has been found in other tissues. Therefore the present study will be conducted on primary cultures of rabbit choroid epithelium. The feasibility of this approach has been demonstrated in the Pl's and co-Pl's laboratories. The principal goal of this application is to examine the biochemical regulation of the two major mechanisms in CSF formation and secretion: the Na+/H+ antiport (located on the basolateral membrane) and the Na+/K+ ATPase on the apical surface of choroid plexus epithelium. Drugs may affect these ion exchange mechanisms via receptors coupled directly to these two mechanisms, or indirectly, via receptors coupled to G-proteins and various second messenger pathways, such as phosphoinositides, Ca++, protein kinase activation, and positive or negative coupling to adenylate cyclase. The overall significance of the present proposal is that it will explore, at the cellular and biochemical level, the neurohumoral control of ion transport in choroid plexus epithelium. This approach is novel and has the potential to considerably increase our understanding of how CSF formation and secretion are controlled. Such knowledge is essential for the design of new drugs that must either avoid or be intended to alter ion transport mechanisms in the choroid plexus and hence CSF function.