G protein-coupled receptor 55 (GPR55) is an orphan Class A receptor which serves
as a target for natural and synthetic cannabinoids. The endogenous agonist for
GPR55 is L-α-lysophosphatidylinositol (LPI). Inhibition of GPR55 by cannabidiol
(CBD) is thought to be a key mechanism by which CBD lessens neuronal
hyperexcitability. GPR55 activation can increase calcium signaling at synaptic
terminals and neuronal cell bodies leading to increased glutamate release. CBD has
been shown to inhibit LPI mediated synaptic calcium rises and thus reducing the
release of glutamate. Excessive glutamate levels have been implicated in the
process of seizure generation. Excessive glutamate levels have been implicated in
the epileptogenesis process. These observations implicate GPR55 as a substrate for
aspects of CBD’s anti-seizure effect. Taken together, these lines of evidence suggest
that pharmacological modulation of GPR55 receptor may provide a novel target that
could imbue anti-seizure effects. Novel GPR55 agonists have recently been
developed and characterized but it is not clear what effect these compounds will
have on seizure activity.
