The human serotonin transporter protein (hSERT) is the conventional drug target of the SSRI antidepressants, e.g., Prozac. However, there is no crystal structure of hSERT bound to an antidepressant. Instead, there is a crystal structure of a distantly related bacterial leucine transporter bound to tricyclic or SSRI antidepressants, which serves as a first approximation for computational drug docking studies when combined with sequence alignments of different SERT family members.
Blakely’s lab created a mutant mouse with a single amino acid substitution in the mouse serotonin transporter protein (“SERT M172″) that disrupted the antidepressant recognition/binding site but left the serotonin transporting function essentially unchanged, as evidenced by a number of carefully controlled experiments. These experiments included examining whether behavioral changes induced by acute treatment (minutes to hours) with antidepressants in wildtype mice are also observed in SERT M172 mouse. Indeed they were not, proving that acute behavioral changes in rodents depend on serotonin transmission.
However, the paper doesn’t address whether SERT M172 mice undergo physiological changes associated with chronic treatment (days to weeks) with antidepressants. These physiological changes include growth of hippocampal neurons and increased expression of neurotrophic factors, e.g., BDNF. The authors are very upfront about this in the discussion, and presumably those experiments are still ongoing.
Whatever the outcome, SERT M172 are an indispensable resource in the study of complex antidepressant pharmacology, because they allow one to test the role of serotonin in specific rodent behavior models of human depression.
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