RECEPTOR-EFFECTOR COUPLING OF SEROTONIN RECEPTORS

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A novel type of serotonin binding site, the 5-HT1C site, has been identified in the mammalian choroid plexus. This binding site is coupled to activation of phosphatidylinositol turnover (Conn et al., Proc. Natl. Acad. Sci. (1986)). In this application we propose to study the molecular and cellular consequences of 5-HT1C receptor activation. We shall measure protein phosphorylation, ion transport activities and intracellular calcium release following receptor activation. Agonist potencies will be examined in this system and the time course of inositol phosphate generation (IP, IP2, IP3) and the effect of GTP will be determined in order to better define the sequence of events which follow receptor activation. A promising new model system for the study of the 5-HT1C receptor will be characterized and developed under this proposal. Choroid plexus tumors develop spontaneously in adult transgenic mice which have integrated copies of SV40 early region genes into their genome. Transgenic mice can pass this trait to their offspring and stable lines of tumor-generating mice have been produced. We have recently discovered that choroid plexus tumors from transgenic mice express high levels of serotonin 5- HT1C receptors. We propose to determine if the 5-HT1C receptor remains coupled to the phosphoinositide hydrolysis system in the tumor and to compare receptor effector coupling in this transformed tissue to normal choroid plexus. In addition, primary cell cultures will be prepared from the tumors and we shall attempt to isolate a continuous cell line expressing the 5- HT1C receptor from these cultures. These cultures will be used as a model systems for the investigation of 5-HT1C receptor dynamics and receptor-effector coupling in living cells. These studies will provide information on receptor-effector coupling with general applicability to phosphoinositide-linked neurotransmitter receptors. Fundamental studies on the properties of this choroid plexus 5-HT1C receptor may also lead to better understanding of two key roles of the choroid plexus: modulation of cerebrospinal fluid production and maintenance of blood-brain barrier functions by the choroid plexus. Such information could lead to new strategies for the treatment of hydrocephalus or new methods of delivering therapeutic agents to the brain.