Emodepside: the anthelmintic’s mode of action and toxicity

Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels play many physiological roles ranging from the maintenance of smooth muscle tone to hearing and neurosecretion. BK channels are tetramers in which the pore-forming α subunit is coded by a single gene (Slowpoke, KCNMA1). In this review, we first highlight the physiological importance of this ubiquitous channel, emphasizing the role that BK channels play in different channelopathies. We next discuss the modular nature of BK channel-forming protein, in which the different modules (the voltage sensor and the Ca(2+) binding sites) communicate with the pore gates allosterically. In this regard, we review in detail the allosteric models proposed to explain channel activation and how the models are related to channel structure. Considering their extremely large conductance and unique selectivity to K(+), we also offer an account of how these two apparently paradoxical characteristics can be understood consistently in unison, and what we have learned about the conduction system and the activation gates using ions, blockers, and toxins. Attention is paid here to the molecular nature of the voltage sensor and the Ca(2+) binding sites that are located in a gating ring of known crystal structure and constituted by four COOH termini. Despite the fact that BK channels are coded by a single gene, diversity is obtained by means of alternative splicing and modulatory β and γ subunits. We finish this review by describing how the association of the α subunit with β or with γ subunits can change the BK channel phenotype and pharmacology. Show more

High-conductance, 'big' potassium (BK) channels encoded by the Slo gene family are among the largest and most complex of the extended family of potassium channels. The family of SLO channels apparently evolved from voltage-dependent potassium channels, but acquired a large conserved carboxyl extension, which allows channel gating to be altered in response to the direct sensing of several different intracellular ions, and by other second-messenger systems, such as those activated following neurotransmitter binding to G-protein-coupled receptors (GPCRs). This versatility has been exploited to serve many cellular roles, both within and outside the nervous system. Show more

The cyclo-octadepsipeptide anthelmintic, emodepside, has pleiotropic effects on the behaviour of the model genetic animal Caenorhabditis elegans: it inhibits locomotion, feeding, egg-laying and slows development. Previous studies on pharyngeal muscle indicated a role for latrophilin-dependent signalling and therefore prompted the suggestion that this is a common effector of this drug's actions. However, whilst a C. elegans functional null mutant for latrophilin (lat-1) is less sensitive to the effect of emodepside on the pharynx it remains sensitive to the inhibitory effects of emodepside on locomotion. Here we show that this is not due to functional redundancy between two C. elegans latrophilins, as the double mutant, lat-2, lat-1, also remains sensitive to the effects of emodepside on locomotion. Therefore, emodepside has latrophilin-independent effects. To define the molecular basis for this we performed a mutagenesis screen. We recovered nine alleles of slo-1, which encodes a Ca(2+)-activated K(+) channel. These mutants were highly resistant to the inhibitory effect of emodepside on both pharyngeal and locomotor activity. The slo-1 alleles are predicted to reduce or eliminate SLO-1 signalling, suggesting that emodepside may signal through a SLO-1-dependent pathway. The observation that gain-of-function slo-1 alleles phenocopy the effects of emodepside, but are not themselves emodepside hypersensitive, favours a model whereby emodepside directly acts through a SLO-1-dependent pathway. Tissue-specific genetic rescue experiments reveal that emodepside acts through SLO-1 expressed in either body wall muscle or in neurones to inhibit locomotion. In contrast, in the pharyngeal system, emodepside acts through SLO-1 in neurones, but not muscle, to inhibit feeding. These data further inform understanding of the mode of action of emodepside and suggest that emodepside causes inhibition of feeding via a neuronal SLO-1-dependent pathway which is facilitated by LAT-1 whilst it signals through a latrophilin-independent, SLO-1-dependent pathway, in either neurones or body wall muscle, to inhibit locomotion. Show more