Acetylcholine Deficiency in Caenorhabditis elegans Induced by Hyperthermia Can Be Compensated by ACh-esterase Inhibition or Activation of GAR-3 mAChRs

Tatyana B Kalinnikova,Marat Kh Gainutdinov,Sergey V Zakharov,Eugenia B Osipova,Rufina R Kolsanova,Rifgat R Shagidullin

doi:10.5539/enrr.v3n3p98

Tatyana B Kalinnikova, Marat Kh Gainutdinov + Show 4 more

Open Access

https://doi.org/10.5539/enrr.v3n3p98

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Abstract

The nervous system is a target of hyperthermic failure of animal behavior. Caenorhabditis elegans can be used as an excellent model organism to investigate mechanisms underlying thermotolerance of nervous system. Inhibition of ACh-esterase by neostigmine produces rise in thermotolerance of C. elegans swimming induced by mechanical stimulus at constant temperature 36 °C. Protection of C. elegans behavior against heat stress by neostigmine indicates that hyperthermia induces ACh deficiency in the C. elegans nervous system which is one of the causes of hyperthermic failure of behavior. Activation of mAChRs by pilocarpine or oxotremorine M elevates behavior thermotolerance similarly with neostigmine while inhibition of these receptors by atropine has opposite effect. These results suggest that ACh protects C. elegans behavior against hyperthermia by binding with mAChRs. It is known that three G-protein coupled ACh receptors of C. elegans (GAR-1, GAR-2 and GAR-3) have sequence homology with five known subtypes of mammalian mAChRs. To identify mAChRs responsible for regulation of behavior response to hyperthermia we investigated effects of loss-of-function mutations in gar-1, gar-2 and gar-3 genes on the sensitivity of behavior thermotolerance to neostigmine and pilocarpine. Among them only loss-of-function gar-3 mutation caused insensitivity of C. elegans behavior thermotolerance to neostigmine and pilocarpine. Thus it is GAR-3 mAChR that mediates rise in behavior thermotolerance produced by ACh-esterase inhibitor neostigmine or agonists of mammalian mAChRs.

Highlights

Temperature is one of the most important variables that determines distribution and abundance of species (Cossins & Bowler, 1987; David, Allemand, Van Herrewege, & Cohet, 1983; Hoffmann, Sørensen, & Loeschke, 2003)
Inhibition of ACh-esterase can be therapeutic for the organism if the complementary rise of ACh concentration is required for the compensation of ACh deficiency which has been established a core pathophysiological feature in Alzheimer’s disease, Parkinson’s disease, vascular dementia and multiple sclerosis’s dementia (Bartus et al, 1982; Harvey et al, 2009; Perry et al, 1978; Tabet, 2006)
In our experiments with C. elegans aldicarb-like toxic effect of neostigmine was shown for concentrations 60-fold higher than those effective for its therapeutic effect revealed in the rise of behavior thermotolerance (Figure 1)

Summary

Introduction

Temperature is one of the most important variables that determines distribution and abundance of species (Cossins & Bowler, 1987; David, Allemand, Van Herrewege, & Cohet, 1983; Hoffmann, Sørensen, & Loeschke, 2003). At extreme high temperature cells and tissues died. Long before this point, invertebrates’ organisms experiencing hyperthermia endangered by impaired neural performance that prevents coordinated behavior and hampers vital motor patterns (Robertson, 2004a, 2004b). It is evident that nervous systems of free-living invertebrates are susceptible to detrimental direct effects of heat stress, as their body temperature is determined to a large extent by environmental temperature

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