Presynaptic nigral GPR55 receptors stimulate [³H]‐GABA release through [³H]‐cAMP production and PKA activation and promote motor behavior

Abstract

Striatal medium-sized spiny neurons express mRNA and protein of GPR55 receptors that stimulate neurotransmitter release; thus, GPR55 could be sent to nigral striatal projections, where it might modulate GABA release and motor behavior. Here, we study the presence of GPR55 receptors at striato-nigral terminals, their modulation of GABA release, their signaling pathway, and their effect on motor activity. By double immunohistochemistry, we found the colocation of GPR55 protein and substance P in the dorsal striatum. In slices of the rat substantia nigra, the GPR55 agonists LPI and O-1602 stimulated [ 3 H]-GABA release induced by high K + depolarization in a dose-dependent manner. The antagonists CID16020046 and cannabidiol prevented agonist stimulation in a dose-dependent way. The effect of GPR55 on nigral [ 3 H]-GABA release was prevented by lesion of the striatum with kainic acid, which was accompanied by a decrement of GPR55 protein in nigral synaptosomes, indicating the presynaptic location of receptors. The depletion of internal Ca 2+ stores with thapsigargin did not prevent the effect of LPI on [ 3 H]-GABA release, but the remotion or chelation of external calcium did. Blockade of Gi, Gs, PLC, PKC, or dopamine D1 receptor signaling proteins did not prevent the effect of GPR55 on release. However, the activation of GPR55 stimulated [ 3 H]-cAMP accumulation and PKA activity. Intranigral unilateral injection of LPI induces contralateral turning. This turning was prevented by CID16020046, cannabidiol, and bicuculline but not by SCH 23390. Our data indicate that presynaptic GPR55 receptors stimulate [ 3 H]-GABA release at striato-nigral terminals through [ 3 H]-cAMP production and stimulate motor behavior.

Elucidation of GPR55-Associated Signaling behind THC and LPI Reducing Effects on Ki67-Immunoreactive Nuclei in Patient-Derived Glioblastoma Cells

“…A correlation between Gβγ signaling and GPR55 has so far not been demonstrated in tumor cells. In murine slice cultures of the substantia nigra, GPR55 signaling induced by LPI or O-1602 was associated with the presynaptic release of [ 3 H] gamma-amino-butyric acid (GABA) by a Gβγ-dependent mechanism [43]. In contrast to the present study, Gβγmediated AC activation with a subsequent cAMP accumulation was assumed to be an underlying mechanism [43], reflecting species-and cell-type-specific differences.…”

Activation of GPR55 Ameliorates Maternal Separation-Induced Learning and Memory Deficits by Augmenting 5-HT Synthesis in the Dorsal Raphe Nucleus of Juvenile Mice

“…GPR55 is a cannabinoid- and lysophosphatidylinositol-sensitive receptor that is expressed throughout the central nervous system and can boost the release of neurotransmitters. , 5-HT is an important neurotransmitter involved in learning and memory. Recent studies have shown that 5-HTergic neurons mainly distributed in the DRN region are essential in early postnatal development, influencing the maturation and modulation of higher-order emotional, sensory, and cognitive circuitry. − Thus, the connection between GPR55 and the 5-HT transmitter release was given priority.…”

GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice

“…In addition, it was recently reported that GPR55 is colocalized with substance P in striatal MSNs using another anti-GPR55 antibody (provided by Bioss). This antibody targets the transmembrane domains of human GPR55 [ 16 ]. However, the GPR55 specificity of this antibody is not tested in GPR55-KO mice.…”

“…The reasons for the lack of efficacy in this study remain unknown. This might be associated with the fact that both Δ 9 -THC and O-1602 are GPR55 agonists and exhibit similar high potency in GTPγS binding assays (Δ 9 -THC EC50: 8 nM; O-1602 EC50: 13 nM) [ 7 , 16 ]. Thus, GPR55 agonism may not be capable of counteracting the effects produced by Δ 9 -THC but may have efficacy against actions produced by other drugs or cannabinoids lacking GPR55 binding profiles by themselves.…”

“…This is supported by several lines of evidence. First, activation of GPR55 increases intracellular Ca ++ levels in neurons in the hippocampus, substantia nigra, and dorsal root ganglia [ 16 , 17 , 39 ], and facilitates glutamate release in the NAc (present study) and hippocampus [ 17 ]. Second, optical stimulation of glutamate terminals in the NAc projected from the paraventricular nucleus of the thalamus is not rewarding, but reward-attenuating or aversive [ 40 ].…”