A Light-Controlled Allosteric Modulator Unveils a Role for mGlu4 Receptors During Early Stages of Ischemia in the Rodent Cerebellar Cortex

Abstract

Metabotropic glutamate receptors (mGlus) are G Protein coupled-receptors that modulate synaptic transmission and plasticity in the central nervous system. Some act as autoreceptors to control neurotransmitter release at excitatory synapses and have become attractive targets for drug therapy to treat certain neurological disorders. However, the high degree of sequence conservation around the glutamate binding site makes the development of subtype-specific orthosteric ligands difficult to achieve. This problem can be circumvented by designing molecules that target specific less well conserved allosteric sites. One such allosteric drug, the photo-switchable compound OptoGluNAM4.1, has been recently employed to reversibly inhibit the activity of metabotropic glutamate 4 (mGlu4) receptors in cell cultures and in vivo. We studied OptoGluNAM4.1 as a negative modulator of neurotransmission in rodent cerebellar slices at the parallel fiber – Purkinje cell synapse. Our data show that OptoGluNAM4.1 antagonizes pharmacological activation of mGlu4 receptors in a fully reversible and photo-controllable manner. In addition, for the first time, this new allosteric modulator allowed us to demonstrate that, in brain slices from the rodent cerebellar cortex, mGlu4 receptors are endogenously activated in excitotoxic conditions, such as the early phases of simulated cerebellar ischemia, which is associated with elevated levels of extracellular glutamate. These findings support OptoGluNAM4.1 as a promising new tool for unraveling the role of mGlu4 receptors in the central nervous system in physio-pathological conditions.

Optical control of neuronal ion channels and receptors

“…PLs have been designed for a huge variety of neurotransmitter receptors and ion channels 8,17,18,48,49 ( Table 1). Examples include blockers of voltage-gated potassium 45,50,51 , sodium 52,53 and calcium 54 channels, activators of GIRK channels 55 , modulators of delayed rectifiers 56 , ATPsensitive 57 and two-pore domain 56 K + channels, activators of TRPV1 channels 58 , agonists and antagonists of ionotropic glutamate receptors (iGluRs) 44,[59][60][61][62] , agonists 11,63 and pore blockers 12 of nicotinic acetylcholine receptors (nAChRs), an agonist of adenosine receptors 64 , an antagonist of GABA A receptors 65 , and allosteric modulators of metabotropic glutamate receptors (mGluRs) [66][67][68][69][70] and of GABA A 71,72 receptors.…”

Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity

“…23 , 24 Currently, the use of light-regulated ligands has enabled site-, organ-, tissue-, or even subcellular-specific targeting of mGlu receptors in strictly defined time applications. 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 …”

Optogluram-2: a subtype-selective photoswitchable positive allosteric modulator for metabotropic glutamate receptor 4

“…This avantgarde technique has been widely applied for research purposes, and several photochromic ligands have been described in the literature allowing the optical control of a wide variety of GPCRs (Panarello et al, 2022;Ricart-Ortega et al, 2019). Currently, the use of light-regulated ligands has enabled site-, organ-, tissue-, or even subcellular-specific targeting of mGlu receptors in strictly defined time applications (Bossi et al, 2018;Donthamsetti et al, 2021;Gómez-Santacana et al, 2017;Pittolo et al, 2014Pittolo et al, , 2019Ricart-Ortega et al, 2020;Rovira et al, 2016;Zussy et al, 2018).…”