Modulation of serotonin transporter function and pharmacology by subunit interactions and an endogenous regulatory factor

Abstract

The serotonin transporter (SERT) mediates clearance of the neuromodulator serotonin (5-HT) following its release. The clinical efficacy of antidepressant drugs that block SERT activity indicates that serotonin transporter function is important for the maintenance of proper mood and affect. Biochemical studies demonstrate that SERTs form oligomeric protein complexes. The present study asks whether SERT function depends on interactions between subunits of the SERT oligomer under physiological conditions. Our data indicate that SERT function is intrinsically cooperative. Interactions between wild-type and mutant SERTs alter intrinsic properties of SERT function such as the Na+-dependent activation of 5-HT transport. Furthermore, the balance of 5-HT transport to 5-HT-induced current is sensitive to interactions between SERT and an as yet unidentified enabling factor. The model we present to explain our data postulates that a ternary complex composed of 5-HT, SERT, and the novel enabling factor dynamically regulates SERT function. Our findings have relevance to SERT function in the native context and transporter biology in general, and could lead to the development of novel therapies for diseases of serotonergic dysfunction.