Tutorial on Moa Mechanisms
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Insecticide Mode of Action Training slide deck IRAC MoA Workgroup Version 1.0, April 2019 1 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright What is an Insecticide’s ‘Mode of Action’? The Mode of action defines the process of how an insecticide works on an insect or mite at a molecular level Why is it good to know the Mode of Action of an Insecticide? Knowing the Mode of action of an insecticide is key to managing resistance The Insecticide Resistance Action Committee (IRAC) is a coordinated industry response to resistance management 2 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright ADME is an important factor in an insecticide’s bioavailability n Absorption q Through the cuticle q Orally through consumption q Inhaled through spiracles as vapor n Distribution Metabolic q Through the body to target sites Enzymes n Metabolism (Break down) q By insect defense mechanisms n Excretion 3 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticides act on key functional proteins that regulate vital processes Target protein e.g. ion channel binding pocket Small molecule insecticide Insecticides act on key functional proteins that regulate vital processes Altered protein function 1. A protein can have more than one binding pocket for small molecules Altered 2. Specific binding pockets can accommodate biological chemicals with different structures response 4 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright The Pro-Insecticide concept A Pro-Insecticide might have negligible activity on the target protein due to protecting groups, but can get metabolized in vivo to its active form. This can be a tool to: • Improve bioavailability Pro-Insecticide Metabolic Enzyme(s) • Enable selective toxicity Insecticide Target protein Altered protein function 5 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Major mechanisms of Insecticide Resistance Metabolic Resistance Metabolic Enzymes and/or Target Insecticide protein Target Site Resistance Insecticide Genetic modifications of Altered Target the target that interfere with target protein binding of the Insecticide protein 6 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Key functional proteins that are targets for Insecticides Ion channels Enzymes Receptors essential for signal biocatalysts bioelectricity transducer ligand + Na+ Ca2+ K+ - or Cl Proteins accelerating chemical reactions Binding of a ligand triggers a response 7 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticide Mode of Action Major classes Nerve & Muscle Growth Respiration Midgut Unknown or Non-Specific 8 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Ion channels are important targets of neuromuscular disruptors Na+ Ca2+ Cl- Cells are surrounded by a cell membrane, which acts - - - like an insulator separating two conducting media K+ Large organic An asymmetric separation of charges across the cell anions membrane makes the inside negative compared to the outside of the cell (membrane potential) Ion channels are pore-forming membrane Na+, Ca2+ proteins that transduce signals by controlling the flux or Cl- of ions across the cell membrane. Their concentration gradients together with the membrane potential • Gating: Trigger for channel determine the direction of ion flux. opening (voltage, ligand, etc.) • Ion selectivity: Ion preference In electrically excitable cells (neurons, muscle cells) of the channel ion channels play an important role in fast signal transduction over long distances 9 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright The Insect Neuromuscular system: Translating a stimulus into (muscle) action Muscle Stimulus ? 10 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Different types of neurons are involved in signal transduction and fine tuning Muscle Stimulus CNS modulatory Ganglion neuron The Central Nervous System (CNS) is the insect’s control center sensory neuron interneuron inhibitory neuron motoneuron 11 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Ion channels play diverse roles within the neuromuscular system Muscle CNS Ganglion 12 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Overview of ion channels targeted by neuromuscular disruptors Muscle CNS Ganglion 13 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright The TRPV channels exist in specialized sensory neurons that detect stretch Muscle CNS modulatory Ganglion neuron Na+, Ca2+ TRPV sensory neuron interneuron inhibitory neuron motoneuron 14 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright TRPV channels play an important role in insect stretch receptor signaling (Chordotonal Organ) • Sight Stimulus • Taste • Smell • Touch • Hearing (antenna) Sensed by • Gravity (antenna) • Proprioception* (joints) stretch receptors • Others sensory neuron *Proprioception is the detection of the relative position and motion of body parts When a doctor tests Insects also have stretch reflexes with a rubber receptors that detect joint hammer (knee jerk reflex) bending forces local stretch receptors are activated that signal to the spinal cord and back to the target muscle. 15 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticides acting on TRPV channels interfere with stretch receptor signaling n TRPV channel modulators affect Chordotonal organs (COs), stretch receptors in the insect joints that sense relative position of body parts (proprioception) Leg extension caused by a TRPV modulator (can be imagined as a ‘molecular’ rubber hammer) n TRPV channels amplify the weak mechanosensory signal in chordotonal neurons 1. Signal detection 2. Signal amplification Mechano- sensory TRPV channel n Modulation of TRPV channels generates continuous chordotonal nerve signals independent of joint movement. This leaves insects deaf and uncoordinated, resulting in rapid feeding cessation, leading to starvation and ultimately death 16 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright TRPV channel and chordotonal organ modulators Group 9: Chordotonal Group 29: organ TRPV channel modulators Chordotonal organ modulators – undefined target site Pymetrozine Flonicamid 9B Pyridine Pyrifluquinazon Afidopyropen azomethine derivatives 9D Pyropenes 29 Flonicamid Flonicamid produces symptoms similar to TRPV channel modulators and like its more active metabolite affects chordotonal organs. However, Flonicamid appears not to act directly on TRPV channels, suggesting a different target site in chordotonal organs. 17 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Overview of ion channels targeted by neuromuscular disruptors Muscle CNS Ganglion 18 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticides acting on Sodium channels Muscle CNS modulatory Ganglion neuron Na+ Sodium Channel sensory neuron interneuron inhibitory neuron motoneuron 19 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Sodium channels play a crucial role in signal propagation in excitable cells Axons are long cable-like parts of the neuron that carry electrical signals to a junction with another cell Na+ Voltage-dependent sodium Sodium channels contain