Molecular physiology of pumiliotoxin sequestration in a poison frog

Poison frogs bioaccumulate alkaloids for chemical defense from their
arthropod diet. Although many alkaloids are accumulated without
modification, some poison frog species can metabolize pumiliotoxin (PTX
251D) into the more potent allopumiliotoxin (aPTX 267A). Despite extensive
research characterizing the chemical arsenal of poison frogs, the
physiological mechanisms involved in the sequestration and metabolism of
individual alkaloids remain unclear. We first performed a feeding
experiment with the Dyeing poison frog (Dendrobates tinctorius) to ask if
this species can metabolize PTX 251D into aPTX 267A and what gene
expression changes are associated with PTX 251D exposure in the
intestines, liver, and skin. We found that D. tinctorius can metabolize
PTX 251D into aPTX 267A, and that PTX 251D exposure changed the expression
level of genes involved in immune system function and small molecule
metabolism and transport. To better understand the functional significance
of these changes in gene expression, we then conducted a series of
high-throughput screens to determine the molecular targets of PTX 251D and
identify potential proteins responsible for metabolism of PTX 251D into
aPTX 267A. Although screens of PTX 251D binding human voltage-gated ion
channels and G-protein coupled receptors were inconclusive, we identified
human CYP2D6 as a rapid metabolizer of PTX 251D in a cytochrome P450
screen. Furthermore, a CYP2D6-like gene had increased expression in the
intestines of animals fed PTX, suggesting this protein may be involved in
PTX metabolism. These results show that individual alkaloids can modify
gene expression across tissues, including genes involved in alkaloid
metabolism. More broadly, this work suggests that specific alkaloid
classes in wild diets may induce physiological changes for targeted
accumulation and metabolism.