The Relationship between Muscarinic and Cannabinoid Receptors in Neuronal Excitability and Epilepsy: A Review

Abstract

Background: Of the seventy million people who suffer from epilepsy, 40 percent of them become resistant to more than one antiepileptic medication and have a higher chance of death. While the classical definition of epilepsy was due to the imbalance between excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic signalling, substantial evidence implicates muscarinic receptors in the regulation of neural excitability.

Summary: Cannabinoids have shown to reduce seizure activity and neuronal excitability in several epileptic models through the activation of muscarinic receptors with drugs which modulate their activity. Cannabinoids also have been effective in reducing antiepileptic activity in pharmaco-resistant individuals; however, the mechanism of its effects in temporal lobe epilepsy is not clear.

Key messages: This review seeks to elucidate the relationship between muscarinic and cannabinoid receptors in epilepsy and neural excitability.

Keywords: Cannabinoids; Crosstalk; Endocannabinoids; Epilepsy; Muscarinic receptors; Neural excitability.

Fig. 1.

Modulation of M channels by both phosphatidylinositol 4,5-bisphosphate (PIP2) and calcium-calmodulin (Ca²⁺-CaM) complex in the superior cervical ganglion (SCG). Fig. 1 shows two mechanisms associated with the inhibition of M channels used by Gq/11 coupled receptors in the superior cervical ganglion (SCG). The M channels are modulated by both phosphatidylinositol 4,5-bisphosphate (PIP2) and calcium-calmodulin (Ca²⁺-CaM) complex, with calcium ions released from the endoplasmic reticulum (ER) through the activation of inositol 1,4,5 trisphosphate receptor (IP3R). Activation of the M1 muscarinic acetylcholine receptors (M1AChR) and AT1 angiotensin II receptors (ATR) are believed to be ineffective releasing Ca²⁺ from the ER due to the lack of spatial co-localisation between the IP3R and IP3 produced by the M1AChR and ATR [50]. Thus, the IP3 dissipates away (yellow arrow) after PIP2 is consumed by PLC. The second pathway is used by purinergic P2Y and bradykinin B receptors which due to their spatial localisation to ER IPR are capable of releasing Ca signals. The released Ca²⁺ binds to neuronal Ca²⁺ sensor-1 (NCS-1) and calmodulin (CaM). NCS-1 promotes PIP2 synthesis via acceleration of PI-4-kinase (green arrow), increasing concentration of PIP2 in the membrane and stabilising PIP2 levels which increases PLC activity. CaM binds to the carboxyl domains of the channel and is speculated to reduce the affinity of PIP2 which then unbinds from the channel since tonic PIP2 concentration is insufficient to maintain association with the channel [50].