Corticosteroid responses of snakes to toxins from toads (bufadienolides) and plants (cardenolides) reflect differences in dietary specializations

Abstract

Toads are chemically defended by cardiotonic steroids known as bufadienolides. Resistance to the acute effects of bufadienolides in snakes that prey on toads is conferred by target-site insensitivity of the toxin's target enzyme, the Na/K-ATPase. Previous studies have focused largely on the molecular mechanisms of resistance but have not investigated the physiological mechanisms or consequences of exposure to the toxins. Adrenal enlargement in snakes often is associated with specialization on a diet of toads. These endocrine glands are partly composed of interrenal tissue, which produces the corticosteroids corticosterone and aldosterone. Corticosterone is the main hormone released in response to stress in reptiles, and aldosterone plays an important role in maintaining ion balance through upregulation of Na/K-ATPase. We tested the endocrine response of select species of snakes to acute cardiotonic steroid exposure by measuring circulating aldosterone and corticosterone concentrations. We found that Rhabdophis tigrinus, which specializes on a diet of toads, responds with lower corticosterone and higher aldosterone compared to other species that exhibit target-site resistance to the toxins but do not specialize on toads. We also found differences between sexes in R. tigrinus, with males generally responding with higher corticosterone and aldosterone than females. This study provides evidence of physiological adaptations, beyond target-site resistance, associated with tolerance of bufadienolides in a specialized toad-eating snake.

Cardiac Glycosides as Immune System Modulators

“…[ 19 , 20 , 21 , 22 ] or oleanders ( Nerium sp.) [ 23 , 24 , 25 , 26 ], but also animals, e.g., in the skin of particular amphibians such as toads ( Bufa bufa and others) [ 27 , 28 ]. Besides, there are equivalents of CGs also in humans, referred to as digitalis-like factors [ 29 , 30 ].…”

Na,K-ATPase α1 and β-subunits show distinct localizations in the nervous tissue of the large milkweed bug

“…The enzyme’s roles in physiological homeostasis are vast, including maintenance of membrane potentials, septate junction formation, control of cell volume, pH homeostasis, and cell signaling (Horisberger 2004 ; Pierre and Xie 2006 ; Paul et al 2007 ; Nie et al 2020 ). Cardiac glycosides (CG) are natural inhibitors of the NKA and can thus have adverse health effects on whole-organismal physiology (Agrawal et al 2012 ; Mohammadi et al 2017 ; Züst et al 2019 ). These compounds are synthesized in genera of numerous plant families (e.g., Apocynaceae, Plantaginaceae, Ranunculaceae, Iridaceae) and in some animals as a defense strategy (Pasteels and Daloze 1977 ; Hollman 1985 ; Krenn and Kopp 1998 ; Steyn and Van Heerden 1998 ).…”

Defence mitigation by predators of chemically defended prey integrated over the predation sequence and across biological levels with a focus on cardiotonic steroids

“…corticosteroids and catecholamines) that results in adrenal enlargement. However, hormonal responses to bufadienolides in Rhabdophus tigrinus show no increase in circulating corticosteroid levels in response to bufadienolide injections [ 152 ]. Alternatively, increased production of the mineralocorticoid hormone aldosterone in the enlarged adrenal glands could compensate for reduction in NKA activity caused by CTS by increasing NKA expression ( figure 4 ) [ 155 , 156 ].…”

“…Alternatively, increased production of the mineralocorticoid hormone aldosterone in the enlarged adrenal glands could compensate for reduction in NKA activity caused by CTS by increasing NKA expression ( figure 4 ) [ 155 , 156 ]. Increased circulating aldosterone has been identified in the Japanese toad-eating snake R. tigrinus [ 152 ], which exhibits highly enlarged adrenal glands [ 151 ]. Furthermore, garter snakes ( Thamnophis elegans ) injected with bufadienolides responded with significantly increased NKA expression in their heart tissue [ 157 ].…”