Receptor-Dependent and Independent Regulation of Voltage-Gated Ca2+ Channels and Ca2+-Permeable Channels by Endocannabinoids in the Brain

Abstract

The activity of specific populations of neurons in different brain areas makes decisions regarding proper synaptic transmission, the ability to make adaptations in response to different external signals, as well as the triggering of specific regulatory pathways to sustain neural function. The endocannabinoid system (ECS) appears to be a very important, highly expressed, and active system of control in the central nervous system (CNS). Functionally, it allows the cells to respond quickly to processes that occur during synaptic transmission, but can also induce long-term changes. The endocannabinoids (eCBs) belong to a large family of bioactive lipid mediators that includes amides, esters, and ethers of long-chain polyunsaturated fatty acids. They are produced “on demand” from the precursors located in the membranes, exhibit a short half-life, and play a key role as retrograde messengers. eCBs act mainly through two receptors, CB1R and CB2R, which belong to the G-protein coupled receptor superfamily (GPCRs), but can also exert their action via multiple non-receptor pathways. The action of eCBs depends on Ca2+, but eCBs can also regulate downstream Ca2+ signaling. In this short review, we focus on the regulation of neuronal calcium channels by the most effective members of eCBs-2-arachidonoylglycerol (2-AG), anandamide (AEA) and originating from AEA-N-arachidonoylglycine (NAGly), to better understand the contribution of ECS to brain function under physiological conditions.

Blockade of L-Type Ca2+ Channel Activity Alleviates Oligodendrocyte Pathology following Brain Injury in Male Rats

“…Signaling mechanisms of Ca 2+ influx and efflux in addition to Ca 2+ binding proteins play diverse roles in the expression of dependent genes, cell survival, proliferation, and differentiation [35]. Transporters of Ca 2+ , VOCCs, ligand gated Ca 2+ channels, Ca 2+ binding proteins, and store-operated Ca 2+ channels maintain normal Ca 2+ concentrations and gradients, which are important for normal Ca 2+ signaling [36]. VOCCs regulate the entry of Ca 2+ into and from a cell, responding to depolarization of the plasma membrane and converting an electrical signal into a chemical one [36].…”

“…Transporters of Ca 2+ , VOCCs, ligand gated Ca 2+ channels, Ca 2+ binding proteins, and store-operated Ca 2+ channels maintain normal Ca 2+ concentrations and gradients, which are important for normal Ca 2+ signaling [36]. VOCCs regulate the entry of Ca 2+ into and from a cell, responding to depolarization of the plasma membrane and converting an electrical signal into a chemical one [36]. VOCCs are multi-subunit structures which include a pore-forming subunit [3].…”

Endocannabinoid signaling in astrocytes

“…Besides CB1 and CB2, other GPCRs such as GPR55 and GPR18 have been proposed as putative cannabinoid receptors (Boczek & Zylinska, 2021 ; Cristino et al, 2020 ). These receptors have been identified in astrocytes, at both mRNA‐ and protein‐level (García‐Gutiérrez et al, 2018 ; Grabiec et al, 2019 ; Gutiérrez‐Rodríguez et al, 2018 ; Sawzdargo et al, 1999 ), however, their functional significance in astrocytes remains largely unexplored.…”

“…In many cases, a single TRP channel can be modulated by distinct stimuli that can modify each other's responses, thereby acting as multiple signal integrators (Venkatachalam & Montell, 2007 ). Amongst TRP channels, there is evidence that cannabinoids can modulate the activity of TRP channels from the vanilloid (TRPV), ankyrin (TRPA), and melastatin (TRPM) subfamilies, namely TRPV1‐4, TRPA1 and TRPM8 (Boczek & Zylinska, 2021 ; Muller et al, 2019 ). In astrocytes, these so‐called “ionotropic cannabinoid receptors” are mainly associated to spatiotemporal coordination of Ca 2+ and sodium (Na + ) transients, that further transduce in various internal signaling cascades with multiple outcomes (Verkhratsky et al, 2014 ).…”

Anticonvulsant Action and Long-Term Effects of Chronic Cannabidiol Treatment in the Rat Pentylenetetrazole-Kindling Model of Epilepsy

“…Besides, it also has an antagonistic effect on GPR55 receptors, partial agonist action on 5-HT1A, and a negative allosteric modulatory effect on opioid receptors (µ and δ) [ 7 ]. Ion channels are also important targets for CBD, the most-studied being the transient receptor potential vanilloid type 1 (TRPV1) and ankyrin type 1 (TRPA1), and T-type voltage-gated calcium channels, which are involved in the regulation of Ca 2+ signaling in the brain [ 3 , 8 , 9 ]. Therefore, CBD treatment could have numerous beneficial outcomes in neuropsychiatric illnesses; however, at present, the only approved indication for CBD is to treat seizures associated with childhood epilepsy syndromes like Lennox–Gastaut and Dravet syndromes [ 10 , 11 ].…”