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Acidification and ?-aminobutyric acid independently alter kairomone-induced behaviour.

ABSTRACT: Exposure to high pCO2 or low pH alters sensation and behaviour in many marine animals. We show that crab larvae lose their ability to detect and/or process predator kairomones after exposure to low pH over a time scale relevant to diel pH cycles in coastal environments. Previous work suggests that acidification affects sensation and behaviour through altered neural function, specifically the action of ?-aminobutyric acid (GABA), because a GABA antagonist, gabazine, restores the original behaviour. Here, however, gabazine resulted in a loss of kairomone detection/processing, regardless of pH. Our results also suggest that GABAergic signalling is necessary for kairomone identification in these larvae. Hence, the mechanism for the observed pH effect varies from the original GABA hypothesis. Furthermore, we suggest that this pH effect is adaptive under diel-cycling pH.

SUBMITTER: Charpentier CL

PROVIDER: S-EPMC5043316 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Acidification and γ-aminobutyric acid independently alter kairomone-induced behaviour.

Charpentier Corie L CL Cohen Jonathan H JH

Royal Society open science 20160921 9

Exposure to high pCO2 or low pH alters sensation and behaviour in many marine animals. We show that crab larvae lose their ability to detect and/or process predator kairomones after exposure to low pH over a time scale relevant to diel pH cycles in coastal environments. Previous work suggests that acidification affects sensation and behaviour through altered neural function, specifically the action of γ-aminobutyric acid (GABA), because a GABA antagonist, gabazine, resto ...[more]

PMID: 27703697

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Project description:Etomidate and propofol are potent general anesthetics that act via GABAA receptor allosteric co-agonist sites located at transmembrane ?+/?- inter-subunit interfaces. Early experiments in heteromeric receptors identified ?N265 (M2-15') on ?2 and ?3 subunits as an important determinant of sensitivity to these drugs. Mechanistic analyses suggest that substitution with serine, the ?1 residue at this position, primarily reduces etomidate efficacy, while mutation to methionine eliminates etomidate sensitivity and might prevent drug binding. However, the ?N265 residue has not been photolabeled with analogs of either etomidate or propofol. Furthermore, substituted cysteine modification studies find no propofol protection at this locus, while etomidate protection has not been tested. Thus, evidence of contact between ?N265 and potent anesthetics is lacking and it remains uncertain how mutations alter drug sensitivity. In the current study, we first applied heterologous ?1?2N265C?2L receptor expression in Xenopus oocytes, thiol-specific aqueous probe modification, and voltage-clamp electrophysiology to test whether etomidate inhibits probe reactions at the ?-265 sidechain. Using up to 300 µM etomidate, we found both an absence of etomidate effects on ?1?2N265C?2L receptor activity and no inhibition of thiol modification. To gain further insight into anesthetic insensitive ?N265M mutants, we applied indirect structure-function strategies, exploiting second mutations in ?1?2/3?2L GABAA receptors. Using ?1M236C as a modifiable and anesthetic-protectable site occupancy reporter in ?+/?- interfaces, we found that ?N265M reduced apparent anesthetic affinity for receptors in both resting and GABA-activated states. ?N265M also impaired the transduction of gating effects associated with ?1M236W, a mutation that mimics ?+/?- anesthetic site occupancy. Our results show that ?N265M mutations dramatically reduce the efficacy/transduction of anesthetics bound in ?+/?- sites, and also significantly reduce anesthetic affinity for resting state receptors. These findings are consistent with a role for ?N265 in anesthetic binding within the ?+/?- transmembrane sites.

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Acidification and ?-aminobutyric acid independently alter kairomone-induced behaviour.

Publications

Acidification and <i>γ</i>-aminobutyric acid independently alter kairomone-induced behaviour.

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