GPCR voltage dependence controls neuronal plasticity and behavior

Abstract

G-protein coupled receptors (GPCRs) play a paramount role in diverse brain functions. Almost 20 years ago, GPCR activity was shown to be regulated by membrane potential in vitro, but whether the voltage dependence of GPCRs contributes to neuronal coding and behavioral output under physiological conditions in vivo has never been demonstrated. Here we show that muscarinic GPCR mediated neuronal potentiation in vivo is voltage dependent. This voltage dependent potentiation is abolished in mutant animals expressing a voltage independent receptor. Depolarization alone, without a muscarinic agonist, results in a nicotinic ionotropic receptor potentiation that is mediated by muscarinic receptor voltage dependency. Finally, muscarinic receptor voltage independence causes a strong behavioral effect of increased odor habituation. Together, this study identifies a physiological role for the voltage dependency of GPCRs by demonstrating crucial involvement of GPCR voltage dependence in neuronal plasticity and behavior. Thus, this study suggests that GPCR voltage dependency plays a role in many diverse neuronal functions including learning and memory.

Lateral axonal modulation is required for stimulus-specific olfactory conditioning in Drosophila

“…33,[64][65][66] GPCRs are known to be activated at extremely low concentrations, ranging in the nM. 67,68 On the other hand, nicotinic receptors operate at higher concentrations, often in the range of mM. 69,70 Thus, it is possible that in the presence of shi ts1 , there is some residual release from KCs at the restrictive temperature that is sufficient to activate mAChR-B but not the nicotinic receptors on downstream neurons.…”

“…Three behavior protocols were used in this study as previously described. 40,67,80 (i) For conditioning experiments, OCT (or OCT:MCH mixture at the ratio of 60:40 or 20:80) and MCH were presented for two minutes from each side of the chamber to test the flies' relative preference. This was followed by a single training session of one minute (see below).…”

A STIM dependent dopamine-insulin axis maintains the larval drive to feed and grow in Drosophila

“…Loss of excitability and the absence of dopamine release from THD’ cells in STIM KO larvae ( Fig. 3A–3C and Fig 4B–4D ) suggests that voltagedependent receptor activity [51] is required to maintain growth in early 2 nd instar larvae. Changes in expression of ion channels and presynaptic components have been observed earlier upon knockdown of STIM in Drosophila and mammalian neurons [52,53].…”

“…We identified the THD' cells as critical for larval feeding from their inability to function in the absence of the SOCE regulator STIM. Loss of excitability and the absence of dopamine -4D) suggests that voltagedependent receptor activity [51] is required to maintain growth in early 2 nd instar larvae.…”

Lateral Axonal Modulation is Required for Stimulus-Specific Olfactory Conditioning in Drosophila

“…A fly's odor preference was calculated as the percentage of time that it spent on one side of the chamber. Three behavior protocols were used in this study as previously described 40,67,68 . (i.)…”