GPR55

Central Nervous System (CNS) Effects
GPR55, often classified as a novel cannabinoid receptor, is expressed in various brain regions, including the hippocampus, thalamus, and cortex. Activation of GPR55 is associated with several CNS effects, primarily through its signaling pathways involving Gq and G12/13 proteins, which lead to increased intracellular calcium via phospholipase C activation and inhibition of M-type potassium currents.

Neuronal Excitation and Neurotransmitter Release: Activation enhances glutamate release in hippocampal slices, suggesting a presynaptic role that increases neuronal excitability Advances in the Physiology of GPR55 in the Central Nervous System. This is mediated by calcium release from intracellular stores, contrasting with the inhibitory effects of CB1/CB2 receptors.
Neural Development: GPR55 is implicated in neural development, influencing morphology and axon growth in retinal projections and spinal cord, indicating a role in sensory system maturation [ibid].
Neuroprotection and Inflammation: The effects are dual-edged; in adult rat hippocampus, GPR55 agonists induce microglia-dependent neuroprotection post-excitotoxic lesions, but under certain conditions, activation can promote neuro-inflammation, potentially lowering pain thresholds [ibid].
Pain Modulation: GPR55 activation shows both pronociceptive and antinociceptive effects. For instance, injections of lysophosphatidylinositol (LPI) into the periaqueductal gray induce pronociceptive effects, while palmitoylethanolamide (PEA) exhibits pain-killing actions, possibly involving GPR55, with ongoing clinical trials for chronic pain [ibid].
Cognitive and Emotional Effects: Central GPR55 stimulation induces anxiolytic-like effects, blocked by antagonists, which induce anxiety. Alterations in GPR55 expression are linked to autism and anxiety models, suggesting a role in emotional regulation [ibid].
Motor Coordination and Memory: GPR55 knockout mice show impaired motor coordination, and bilateral infusions of CID16020046 in the dorsolateral striatum impair rat performance in the Rotarod test. GPR55 blockade shifts learning curves in T-maze tasks, indicating a role in procedural memory, though motor effects require further investigation [ibid].

Cardiovascular System Effects
GPR55's role in the cardiovascular system is less definitive, with conflicting evidence on its impact on blood pressure and cardiac function.

Blood Pressure Regulation: Initial hopes linked GPR55 to the hypotensive effects of cannabinoids, but GPR55 knockout mice showed no altered blood pressure regulation after administration of abnormal cannabidiol, suggesting controversy GPR55 - Wikipedia. However, some studies indicate hypotensive effects upon activation GPR55 - an overview | ScienceDirect Topics.
Cardiac Function: Research on GPR55 knockout mice revealed reduced contractile reserve in response to dobutamine, indicating a role in cardiac contractility GPR55 EXERTS DIFFERENTIAL EFFECTS ON CARDIAC ADRENOCEPTOR SUBTYPES IN MICE | Heart. This suggests GPR55 may modulate adrenoceptor responsiveness.
Atherosclerosis: Activation in macrophages increases lipid accumulation and proinflammatory responses, potentially exacerbating atherosclerosis, as seen with the agonist O-1602 enhancing CD36- and SRB-I-mediated lipid uptake and blocking cholesterol efflux Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses | PLOS ONE.

Metabolic System Effects
GPR55's role in metabolism is increasingly recognized, particularly in energy balance and glucose homeostasis, making it a potential target for metabolic disorders.

Insulin Secretion: Activation by agonists like O-1602 and abnormal cannabidiol (Abn-CBD) increases glucose-induced insulin secretion in pancreatic β-cells, mediated through inositol trisphosphate-mediated calcium release G-protein coupled receptor 55 agonists increase insulin secretion | ScienceDirect. Studies on isolated mouse and human islets confirm this effect, with GPR55 knockout reducing the response GPR55-dependent stimulation of insulin secretion from isolated mouse and human islets of Langerhans | PubMed.
Glucose Homeostasis and Adiposity: GPR55 activation improves glucose tolerance in preclinical models, and its deficiency is associated with increased adiposity and impaired insulin signaling in peripheral tissues, suggesting a role in regulating body weight and metabolic health GPR55 deficiency is associated with increased adiposity and impaired insulin signaling | PMC. This is supported by reviews focusing on energy balance GPR55: a new promising target for metabolism? | Journal of Molecular Endocrinology.

Gastrointestinal System Effects
GPR55's presence in the gastrointestinal tract, particularly on myenteric neurons, suggests a role in gut motility and function.

Motility: Activation, particularly with agonists like O-1602, reduces gastrointestinal motility, with significant effects on colonic contractions. For instance, O-1602 concentration-dependently reduced evoked contractions in mouse and human colon muscle strips, an effect reversed by the antagonist cannabidiol (CBD) A role for O-1602 and G protein-coupled receptor GPR55 in the control of colonic motility in mice | PMC. Studies in rodents also show GPR55 ligands influencing GI transit, with implications for conditions like septic ileus A novel CB receptor GPR55 and its ligands are involved in regulation of gut movement in rodents | PubMed.

Immune System Effects
GPR55's role in the immune system is complex, with evidence for both pro-inflammatory and anti-inflammatory actions, depending on the context.

Inflammation: Some studies suggest anti-inflammatory effects, such as in experimental models of Dravet syndrome and Parkinson's disease where CBD, acting as a GPR55 antagonist, elicited anti-inflammatory responses GPR55 - an overview | ScienceDirect Topics. Conversely, other research indicates a pro-inflammatory role, with GPR55 activation enhancing cytokine production and inflammatory responses in macrophages, as seen in atherosclerosis models Activation of GPR55 Receptors Exacerbates oxLDL-Induced Lipid Accumulation and Inflammatory Responses | PLOS ONE. In a multiple sclerosis model, GPR55 knockout reduced disease severity, suggesting a pro-inflammatory contribution [ibid]. This duality is further highlighted in reviews discussing GPR55 as a potential therapeutic target in inflammation, with context-dependent effects GPR55 – a putative “type 3” cannabinoid receptor in inflammation | De Gruyter Brill.

Cancer-Related Effects
GPR55's role in cancer is another area of interest, with implications for tumor growth and progression.

Tumor Growth: Activation is associated with increased tumor growth in certain cancers, such as glioma, where GPR55 knockdown delayed tumor growth in animal models GPR55 - an overview | ScienceDirect Topics. This is linked to its signaling pathways promoting proliferation and cytoskeletal modulation, making it a potential target for anti-cancer therapeutics [ibid].