Cellular signal transduction by anandamide and 2-arachidonoylglycerol

doi:10.1016/S0009-3084(00)00187-0

Chemistry and Physics of Lipids

Volume 108, Issues 1–2, November 2000, Pages 53-70

https://doi.org/10.1016/S0009-3084(00)00187-0 Get rights and content

Abstract

Anandamide (arachidonylethanolamide) and 2-arachidonoylglycerol mediate many of their actions via either CB₁ or CB₂ cannabinoid receptor subtypes. These agonist-receptor interactions result in activation of G proteins, particularly those of the G_i/o family. Signal transduction pathways that are regulated by these G proteins include inhibition of adenylyl cyclase, regulation of ion currents (inhibition of voltage-gated L, N and P/Q Ca²⁺-currents; activation of K⁺ currents); activation of focal adhesion kinase (FAK), mitogen activated protein kinase (MAPK) and induction of immediate early genes; and stimulation of nitric oxide synthase (NOS). Other effects of anandamide and/or 2-arachidonoylglycerol that are not mediated via cannabinoid receptors include inhibition of L-type Ca²⁺ channels, stimulation of VR₁ vanilloid receptors, transient changes in intracellular Ca²⁺, and disruption of gap junction function. Cardiovascular regulation by anandamide appears to occur by a variety of receptor-mediated and non-receptor-mediated mechanisms. This review will describe and evaluate each of these signal transduction pathways and mechanisms.

Section snippets

CB₁ and CB₂ cannabinoid receptor-mediated signal transduction

As the result of the discovery that anandamide possessed affinity for the CB₁ receptor in the 100 nM–1 μM range (Devane et al., 1992), signal transduction mechanisms most closely attributed to the CB₁-mediated regulation of the G_i/o were determined. Stimulation of G protein coupled receptors by agonists promotes the removal of GDP from the guanine nucleotide binding site on the G_i/o∀ protein, allowing subsequent binding of GTP to that site. Direct activation of G proteins, particularly those of

L-type Ca²⁺ channels

Prior to the recognition of arachidonylethanolamide as a signal transduction agent and its naming as anandamide (Devane et al., 1992), a lipid fraction was isolated from bovine brain that competed for [³H]nitrendipine binding to L-type Ca²⁺ channels in rat cardiac membranes (Janis et al., 1988). The ‘inhibitory fraction from brain’ was able to block L-type Ca²⁺ channel currents in GH₃ pituitary cells, and the isolated material was described in a US patent filed by R.A. Janis and D.E. Johnson as

Interaction of anandamide with the vanilloid VR₁ receptor

The VR₁ vanilloid receptor can be categorized with the transient release potential family of store-operated calcium channels based upon sequence homology and its function as a cation channel that promotes calcium influx into sensory nerve terminals (reviewed by Szallasi and Blumberg, 1999). The VR₁ vanilloid receptor is a 6-membrane spanning protein with intracellular N- and C-terminals and a pore-loop between the 5th and 6th transmembrane helices. It is found on sensory neurons where the

Gap junction function

Evidence is accumulating to support a non-CB₁/-CB₂ action of anandamide and the mono-unsaturated fatty acid amide oleamide to inhibit gap junction function (Venance et al., 1995, Guan et al., 1997, Boger et al., 1998). In cultured mouse embryonic striatal astrocytes, gap junction conductance was measured with the double whole-cell recording technique and by dye permeability (Venance et al., 1995). In those studies, 5 μM anandamide, but not the potent cannabinoid receptor agonists CP55940 or

Intracellular Ca²⁺ transients

In cultured embryonic rat striatal astrocytes, (R)-methanandamide inhibited both the peak increase in intracellular Ca²⁺ as well as the sustained plateau in response to stimulation of ET₁ endothelin or metabotropic glutamate receptors (Venance et al., 1997). The effect was not due to an inhibition of phospholipase C activity, but appeared to be distal to IP₃ production and predominantly involved IP₃ receptor-releasable stores of Ca²⁺ (Venance et al., 1997). These investigators interpreted this

Other non-CB₁/-CB₂ receptor-mediated effects

Anandamide has been shown to regulate signal transduction pathways via non-CB₁/-CB₂ receptor mediated mechanism(s). Anandamide (3–100 μM) and other cannabinoid agonists at high concentrations evoked arachidonic acid release and caused an inhibition of [³H]arachidonic acid uptake in CHO and L cells devoid of cannabinoid receptors (Felder et al., 1992, Felder et al., 1993). [³H]Arachidonic acid release from human monocytes and J774 macrophages occurred only at high anandamide concentrations

Cardiovascular signal transduction mechanisms proposed for anandamide and 2-arachidonoylglycerol

Anandamide evokes smooth muscle relaxation in various endothelium-intact and denuded arterial preparations, and evidence for this has been reviewed (Wagner et al., 1998a). Anandamide and its analogs mimicked the hypotensive effects of Δ⁹-tetrahydrocannabinol in various models of conscious or anesthetized normotensive, or spontaneously hypertensive, rats (Varga et al., 1996, Lake et al., 1997a, Lake et al., 1997b). In anesthetized rats, anandamide evoked changes in blood pressure and heart rate

Acknowledgements

Drs Howlett and Mukhopadhyay have been supported by NIDA grants K05-DA00182 and R01-DA03690. We thank Gerald H. Wilken for technical assistance with the experiments in Fig. 1.

References (95)

J. Barg et al.
Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides
Eur. J. Pharmacol.
(1995)
M. Bayewitch et al.
The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling
FEBS Lett.
(1995)
E.V. Berdyshev et al.
Influence of fatty acid ethanolamides and Δ⁹-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells
Eur. J. Pharmacol.
(1997)
B.A. Berglund et al.
Structural requirements for arachidonylethanolamide interaction with CB₁ and CB₂ cannabinoid receptors: pharmacology of the carbonyl and ethanolamide groups
Prostaglandins Leukot. Essent. Fatty Acids
(1998)
A.S. Bloom et al.
Nonclassical and endogenous cannabinoids: effects on the ordering of brain membranes
Neurochem. Res.
(1997)
D.L. Boger et al.
Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide
Proc. Natl. Acad. Sci. USA
(1998)
D.L. Boger et al.
Arachidonic acid amide inhibitors of gap junction cell-cell communication
Bioorg. Med. Chem. Lett.
(1999)
D.L. Boring et al.
Cerebrodiene, arachidonyl ethanolamide, and hybrid structures: potential for interaction with brain cannabinoid receptors
Prostaglandins Leukot. Essent. Fatty Acids
(1996)
M. Bouaboula et al.
Stimulation of cannabinoid receptor CB₁ induces krox-24 expression in human astrocytoma cells
J. Biol. Chem.
(1995)
M. Bouaboula et al.
Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB₁
Biochem. J.
(1995)

DiMarzo, V., DePetrocellis, L., Bisogno, T., Maurelli, S., 1997. The endogenous cannabimimetic eicosanoid, anandamide,...

V. DiMarzo et al.

Interactions between synthetic vanilloids and the endogenous cannabinoid system

FEBS Lett.

(1998)

P. Fan

Cannabinoid agonists inhibit the activation of 5-HT₃ receptors in rat nodose ganglion neurons

J. Neurochem.

(1995)

C.C. Felder et al.

Cannabinoid agonists stimulate both receptor- and non-receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones

Mol. Pharmacol.

(1992)

C.C. Felder et al.

Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction

Proc. Natl. Acad. Sci. USA

(1993)

C.C. Felder et al.

Comparison of the pharmacology and signal transduction of the human cannabinoid CB₁ and CB₂ receptors

Mol. Pharmacol.

(1995)

C. Fimiani et al.

Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release

Cell. Signal.

(1999)

D. Fulton et al.

Evidence against anandamide as the hyperpolarizing factor mediating the nitric oxide-independent coronary vasodilator effect of bradykinin in the rat

J. Pharmacol. Exp. Ther.

(1998)

D. Gebremedhin et al.

Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca²⁺ channel current

Am. J. Physiol.

(1999)

G. Griffin et al.

Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5′-O-(3-[³⁵S]thio)-triphosphate binding assay in rat cerebellar membranes

J. Pharmacol. Exp. Ther.

(1998)

W. Gonsiorek et al.

Endocannabinoid 2-arachidonyl glycerol is a full agonist through human Type 2 cannabinoid receptor: antagonism by anandamide

Mol. Pharmacol.

(2000)

X. Guan et al.

The sleep-inducing lipid oleamide deconvolutes gap junction communication and calcium wave transmission in glial cells

J. Cell Biol.

(1997)

M. Guzman et al.

Effects of cannabinoids on energy metabolism

Life Sci.

(1999)

A.J. Hampson et al.

Dual effects of anandamide on NMDA receptor-mediated responses and neurotransmission

J. Neurochem.

(1998)

C.J. Hillard et al.

Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB₁)

J. Pharmacol. Exp. Ther.

(1999)

E.J.N. Ishac et al.

Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB₁ receptors on peripheral sympathetic nerves

Br. J. Pharmacol.

(1996)

R.A. Janis et al.

Isolation and characterization of a fraction from brain that inhibits 1,4-[³H]dihydropyridine binding and L-type calcium channel current

FEBS Lett.

(1988)

Z. Jarai et al.

Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB₁ or CB₂ receptors

Proc. Natl. Acad. Sci. USA

(1999)

Z. Jarai et al.

Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice

Hypertension

(2000)

A. Jarrahian et al.

Arachidonylethanolamide (anandamide) binds with low affinity to dihydropyridine binding sites in brain membranes

Prostaglandins Leukot. Essent. Fatty Acids

(1997)

Y.J. Jeon et al.

Attenuation of inducible nitric oxide synthase gene expression by Δ⁹-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-6B/Rel activation

Mol. Pharmacol.

(1996)

D.E. Johnson et al.

Isolation, identification and synthesis of an endogenous arachidonic amide

Prostaglandins Leukot. Essent. Fatty Acids

(1993)

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¹: Present address: J.L. Chambers Biomedical and Biotechnology Research Institute, North Carolina Central University, 1801 Fayetteville St., Durham, NC 27707, USA.

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ReviewCellular signal transduction by anandamide and 2-arachidonoylglycerol

Abstract

Section snippets

CB1 and CB2 cannabinoid receptor-mediated signal transduction

L-type Ca2+ channels

Interaction of anandamide with the vanilloid VR1 receptor

Gap junction function

Intracellular Ca2+ transients

Other non-CB1/-CB2 receptor-mediated effects

Cardiovascular signal transduction mechanisms proposed for anandamide and 2-arachidonoylglycerol

Acknowledgements

Cannabinomimetic behavioral effects of and adenylate cyclase inhibition by two new endogenous anandamides

Eur. J. Pharmacol.

The peripheral cannabinoid receptor: adenylate cyclase inhibition and G protein coupling

FEBS Lett.

Influence of fatty acid ethanolamides and Δ9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells

Eur. J. Pharmacol.

Structural requirements for arachidonylethanolamide interaction with CB1 and CB2 cannabinoid receptors: pharmacology of the carbonyl and ethanolamide groups

Prostaglandins Leukot. Essent. Fatty Acids

Nonclassical and endogenous cannabinoids: effects on the ordering of brain membranes

Neurochem. Res.

Chemical requirements for inhibition of gap junction communication by the biologically active lipid oleamide

Proc. Natl. Acad. Sci. USA

Arachidonic acid amide inhibitors of gap junction cell-cell communication

Bioorg. Med. Chem. Lett.

Cerebrodiene, arachidonyl ethanolamide, and hybrid structures: potential for interaction with brain cannabinoid receptors

Prostaglandins Leukot. Essent. Fatty Acids

Stimulation of cannabinoid receptor CB1 induces krox-24 expression in human astrocytoma cells

J. Biol. Chem.

Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1

Biochem. J.

Signalling pathway associated with stimulation of CB2 peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinases and induction of Krox-24 expression

Eur. J. Biochem.

Cannabinoid receptor CB1 activates the Na+/H+ exchanger NHE-1 isoform via Gi-mediated mitogen activated protein kinase signaling transduction pathways

FEBS Lett.

Cannabinoid receptor agonist efficacy for stimulating [35S]GTPγS binding to rat cerebellar membranes correlates with agonist-induced decreases in GDP affinity

J. Biol. Chem.

Relative efficacies of cannabinoid CB1 receptor agonists in the mouse brain

Eur. J. Pharmacol.

Cannabinoid CB1 receptor and endothelium-dependent hyperpolarization in guinea-pig carotid, rat mesenteric and porcine coronary arteries

Br. J. Pharmacol.

The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication

J. Physiol.

Modification of 5-HT2 receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors

Neuropharmacology

Role of cyclic AMP in the actions of cannabinoid receptors

Biochem. Pharmacol.

Effects of anandamide on cannabinoid receptors in rat brain membranes

Biochem. Pharmacol.

Tetrahydrocannabinol inhibition of macrophage nitric oxide production

Biochem. Pharmacol.

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation

Proc. Natl. Acad. Sci. USA

Regulation of a neuronal form of focal adhesion kinase by anandamide

Science

The endogenous cannabinoid anandamide is a lipid messenger activating cell growth via a cannabinoid receptor-independent pathway in hematopoietic cell lines

FEBS Lett.

Production and physiological actions of anandamide in the vasculature of the rat kidney

J. Clin. Invest.

Isolation and structure of a brain constituent that binds to the cannabinoid receptor

Science

Interactions between synthetic vanilloids and the endogenous cannabinoid system

FEBS Lett.

Cannabinoid agonists inhibit the activation of 5-HT3 receptors in rat nodose ganglion neurons

J. Neurochem.

Cannabinoid agonists stimulate both receptor- and non-receptor-mediated signal transduction pathways in cells transfected with and expressing cannabinoid receptor clones

Mol. Pharmacol.

Anandamide, an endogenous cannabimimetic eicosanoid, binds to the cloned human cannabinoid receptor and stimulates receptor-mediated signal transduction

Proc. Natl. Acad. Sci. USA

Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors

Mol. Pharmacol.

Morphine and anandamide stimulate intracellular calcium transients in human arterial endothelial cells: coupling to nitric oxide release

Cell. Signal.

Evidence against anandamide as the hyperpolarizing factor mediating the nitric oxide-independent coronary vasodilator effect of bradykinin in the rat

J. Pharmacol. Exp. Ther.

Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current

Am. J. Physiol.

Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5′-O-(3-[35S]thio)-triphosphate binding assay in rat cerebellar membranes

J. Pharmacol. Exp. Ther.

Endocannabinoid 2-arachidonyl glycerol is a full agonist through human Type 2 cannabinoid receptor: antagonism by anandamide

Review
Cellular signal transduction by anandamide and 2-arachidonoylglycerol

CB₁ and CB₂ cannabinoid receptor-mediated signal transduction

L-type Ca²⁺ channels

Interaction of anandamide with the vanilloid VR₁ receptor

Intracellular Ca²⁺ transients

Other non-CB₁/-CB₂ receptor-mediated effects

Influence of fatty acid ethanolamides and Δ⁹-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells

Structural requirements for arachidonylethanolamide interaction with CB₁ and CB₂ cannabinoid receptors: pharmacology of the carbonyl and ethanolamide groups

Stimulation of cannabinoid receptor CB₁ induces krox-24 expression in human astrocytoma cells

Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB₁

Signalling pathway associated with stimulation of CB₂ peripheral cannabinoid receptor. Involvement of both mitogen-activated protein kinases and induction of Krox-24 expression

Cannabinoid receptor CB₁ activates the Na⁺/H⁺ exchanger NHE-1 isoform via G_i-mediated mitogen activated protein kinase signaling transduction pathways

Cannabinoid receptor agonist efficacy for stimulating [³⁵S]GTPγS binding to rat cerebellar membranes correlates with agonist-induced decreases in GDP affinity

Relative efficacies of cannabinoid CB₁ receptor agonists in the mouse brain

Cannabinoid CB₁ receptor and endothelium-dependent hyperpolarization in guinea-pig carotid, rat mesenteric and porcine coronary arteries

Modification of 5-HT₂ receptor mediated behaviour in the rat by oleamide and the role of cannabinoid receptors

Cannabinoid agonists inhibit the activation of 5-HT₃ receptors in rat nodose ganglion neurons

Comparison of the pharmacology and signal transduction of the human cannabinoid CB₁ and CB₂ receptors

Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca²⁺ channel current

Evaluation of cannabinoid receptor agonists and antagonists using the guanosine-5′-O-(3-[³⁵S]thio)-triphosphate binding assay in rat cerebellar membranes

Synthesis and characterization of potent and selective agonists of the neuronal cannabinoid receptor (CB₁)

Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB₁ receptors on peripheral sympathetic nerves

Isolation and characterization of a fraction from brain that inhibits 1,4-[³H]dihydropyridine binding and L-type calcium channel current

Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB₁ or CB₂ receptors

Attenuation of inducible nitric oxide synthase gene expression by Δ⁹-tetrahydrocannabinol is mediated through the inhibition of nuclear factor-6B/Rel activation