Fig. 4.

Expression pattern of monepantel receptor in C. elegans, and model for the interaction of the drug and its receptor in H. contortus. (A) Expression of ACR-23. Transgenic L4 larva containing an integrated array expressing the acr-23 open reading frame fused to the green fluorescent protein gene. Transgene expression was mainly visible in the body wall muscle bundles (white arrows), and in two unidentified cells, which are neither the PLM neurons nor body wall muscle cells nuclei (white arrowheads in the inset, which shows a magnification of the tail). Gut granules emit yellow autofluorescence. (B) Image taken by differential interference contrast microscopy. Black arrows and arrowhead indicate the pharyngeal bulbs and the position of the developing vulva, respectively. The inset shows a detail of the tail, ventral view. The rectal opening (asterisk) is immediately anterior to the two GFP labelled cells in A. Bar, 50 μm. (C) Hypothetical model for the interaction of monepantel with its target receptor in H. contortus, Hco-MPTL-1. In the resting situation, the MPTL-1 receptor is closed and no ion is flowing through the channel. The neurons or muscle cells are silent respectively not contracted. When the receptor-agonist (e.g. choline or betaine) is released from a presynaptic or potentially an epidermal cell, it binds to the MPTL-1 receptors present at the postsynaptic nerve cell or at the body wall muscle cell. An inflow of Na⁺ ions enters the cell through the pore formed by the opened receptor, creating a depolarization of the cell membrane. This leads to the stimulation of the nerve cell or to the pulse contraction of the muscle cell and finally a controlled movement. The interaction of monepantel with MPTL-1 results in a permanent stimulation or contraction creating a spastic paralysis of the nematode and its expulsion from the host. The ancillary protein RIC-3, which is resident in the endoplasmic reticulum (ER), may play a role for the assembly of the receptor containing MPTL-1. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)