G-protein-coupled serotonin receptors: Signal transduction mechanisms and importance in heart failure

Modulation of neurohormonal regulation of heart function is a cornerstone in current pharmacological treatment of heart failure. Although several new potential neurohormonal drug targets have been identified and are being evaluated, this approach has been far from fully exploited. Unpublished results from our labs have identified three receptor genes which are highly upregulated in heart failure, and the changed expression of which leads to major changes in contractile responses to neurohormonal stimulati on in heart failure. One of these genes is currently under evaluation as a drug target in our labs (patent pending). On this basis, the aim of the current research proposal is to identify and further evaluate as drug targets genes which are important for neurohormonal responsiveness and which are modulated in heart failure. The relevant signal transduction mechanisms will be explored, with emphasis on novel signalling pathways from the Gs-coupled serotonin receptors 5-HT4 and 5-HT7 leading to activation o f Ras and MAP kinases. Furthermore, the importance of agonist-independent (constitutive) receptor activity will be explored. We found that constitutively active human 5-HT7 but not 5-HT4 receptors attenuate adenylyl cyclase stimulation through other rece ptors, and the mechanism of this attenuation will be explored by several approaches.