The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein

Porcella, Anna; Maxia, Chiara; Gessa, Gian Luigi; Pani, Luca

doi:10.1046/j.1460-9568.2000.01027.x

Cited by 92 publications

(60 citation statements)

References 31 publications

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“…This study demonstrates that endogenously expressed CB 1 receptors in ocular hTM cells are capable of pleiotropy in signal transduction in an agonist-dependent manner by coupling to either G q/11 or G i/o to increase [Ca 2 þ ] i and activate ERK1/2. Cannabinoid receptors and their endogenous ligands, anandamide/arachidonylethanolamide and 2-AG, are present in tissues of both the anterior and posterior chambers of the mammalian eye (Bisogno et al, 1999;Straiker et al, 1999;Lu et al, 2000;Porcella et al, 2000;Chen et al, 2005). This distribution suggests they may play an important role in a diverse array of ocular functions including IOP regulation (reviewed in Tomida et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…The presence of CB 1 receptors in the tissues of both inflow and outflow pathways in the eye (Straiker et al, 1999;Porcella et al, 2000;Stamer et al, 2001) indicates that activation of CB 1 at multiple sites probably contributes to a net decrease in IOP. Consistent with this, changes in aqueous inflow (Chien et al, 2003) and outflow (Colasanti, 1990;Beilin et al, 2000) have been observed following cannabinoid administration.…”

Section: Discussionmentioning

confidence: 99%

“…However, the cloning of two G-protein-coupled receptors, CB 1 and CB 2 (Matsuda et al, 1990;Munro et al, 1993), that specifically bind cannabinoids, precipitated the discovery of the endocannabinoid system, consisting of cannabinoid receptors, endogenous endocannabinoids and the enzymes required for their synthesis and degradation (Piomelli, 2003;Jonsson et al, 2006). CB 1 cannabinoid receptors (CB 1 ) are present in ocular tissues of both the inflow and outflow pathways, including the TM (Straiker et al, 1999;Porcella et al, 2000;Stamer et al, 2001). The functional relevance of CB 1 in TM tissue is still unclear, although activation of CB 1 has been found to activate Ca 2 þ -sensitive K þ channels in human TM cells and relax bovine TM tissue strips (Stumpff et al, 2005), both of which may contribute to alterations in outflow resistance and IOP.…”

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confidence: 99%

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Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

McIntosh

Hudson

Yegorova

et al. 2007

British J Pharmacology

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Background and purpose: Trabecular meshwork (TM) is an ocular tissue involved in the regulation of aqueous humour outflow and intraocular pressure (IOP). CB 1 receptors (CB 1 ) are present in TM and cannabinoid administration decreases IOP. CB 1 signalling was investigated in a cell line derived from human TM (hTM). Experimental approach: CB 1 signalling was investigated using ratiometric Ca 2 þ imaging, western blotting and infrared In-Cell Western analysis. Key results: WIN55212-2, a synthetic aminoalkylindole cannabinoid receptor agonist (10-100 mM) increased intracellular Ca 2 þ in hTM cells. WIN55,212-2-mediated Ca 2 þ increases were blocked by AM251, a CB 1 antagonist, but were unaffected by the CB 2 antagonist, AM630. The WIN55,212-2-mediated increase in [Ca 2 þ ] i was pertussis toxin (PTX)-insensitive, therefore, independent of G i/o coupling, but was attenuated by a dominant negative Ga q/11 subunit, implicating a G q/11 signalling pathway. The increase in [Ca 2 þ ] i was dependent upon PLC activation and mobilization of intracellular Ca 2 þ stores. A PTXsensitive increase in extracellular signal-regulated kinase (ERK1/2) phosphorylation was also observed in response to WIN55,212-2, indicative of a G i/o signalling pathway. CB 1 -G q/11 coupling to activate PLC-dependent increases in Ca 2 þ appeared to be specific to WIN55,212-2 and were not observed with other CB 1 agonists, including CP55,940 and methanandamide. CP55940 produced PTX-sensitive increases in [Ca 2 þ ] i at concentrations Z15 mM, and PTX-sensitive increases in ERK1/2 phosphorylation. Conclusions and implications: This study demonstrates that endogenous CB 1 couples to both G q/11 and G i/o in hTM cells in an agonist-dependent manner. Cannabinoid activation of multiple CB 1 signalling pathways in TM tissue could lead to differential changes in aqueous humour outflow and IOP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

McIntosh

Hudson

Yegorova

et al. 2007

British J Pharmacology

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“…Cannabinoids act on G-protein-coupled receptors (CB1 and CB2). RT-PCR and in situ hybridization indicate the presence of both CB1 and CB2 receptors throughout the retina (Lu et al, 2000;Buckley et al, 1998;Porcella et al, 2000). CB1 receptor antibodies label many neurons in the retina, including rod and cone terminals (Straiker et al, 1999;Yazulla et al, 1999;Straiker and Sullivan, 2003).…”

Section: Cannabinoids-cannabinoidsmentioning

confidence: 99%

Synaptic transmission at retinal ribbon synapses

Heidelberger

Thoreson

Witkovsky

2005

Progress in Retinal and Eye Research

209

231

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The molecular organization of ribbon synapses in photoreceptors and ON bipolar cells is reviewed in relation to the process of neurotransmitter release. The interactions between ribbon synapseassociated proteins, synaptic vesicle fusion machinery and the voltage-gated calcium channels that gate transmitter release at ribbon synapses are discussed in relation to the process of synaptic vesicle exocytosis. We describe structural and mechanistic specializations that permit the ON bipolar cell to release transmitter at a much higher rate than the photoreceptor does, under in vivo conditions. We also consider the modulation of exocytosis at photoreceptor synapses, with an emphasis on the regulation of calcium channels.

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“…Among the GPCRs identified in the CBE are A3 adenosine (Mitchell et al, 1999;Avila et al, 2001) and cannabinoid 1 (CB1) receptors (Porcella et al, 1998;Straiker et al, 1999;Stamer et al, 2001). Agonists for these receptors have been reported to alter intraocular pressure (IOP) (Crosson, 1995(Crosson, , 2001Crosson & Petrovich, 1999;Pate et al, 1996;Tian et al, 1997;Porcella et al, 2000;2001;Song & Slowey, 2000;Avila et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

A3 adenosine and CB1 receptors activate a PKC‐sensitive Cl⁻ current in human nonpigmented ciliary epithelial cells via a Gβγ‐coupled MAPK signaling pathway

Shi¹,

Szcześniak²,

Mao³

et al. 2003

British J Pharmacology

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1 We examined A3 adenosine and CB1 cannabinoid receptor-coupled signaling pathways regulating Cl À current in a human nonpigmented ciliary epithelial (NPCE) cell line. 2 Whole-cell patch-clamp recordings demonstrated that the A3 receptor agonist, IB-MECA, activates an outwardly rectifying Cl À current (I Cl,Aden ) in NPCE cells, which was inhibited by the adenosine receptor antagonist, CGS-15943 or by the protein kinase C (PKC) activator, phorbol 12,13 dibutyrate (PDBu). 3 Treatment of NPCE cells with pertussis-toxin (PTX), or transfection with the COOH-terminus of b-adrenergic receptor kinase (ct-bARK), inhibited I Cl,Aden . The phosphatidyl inositol 3-kinase (PI3K) inhibitor, wortmannin, had no effect on I Cl,Aden ; however, the mitogen-activated protein kinase kinase (MEK) inhibitor, PD98059, inhibited I Cl,Aden . 4 Reverse transcription -polymerase chain reaction experiments and immunocytochemistry confirmed mRNA and protein expression for the CB1 receptor in NPCE cells, and the CB1 receptor agonist, Win 55,212-2, activated a PDBu-sensitive Cl À current (I Cl,Win ). 5 Transfection of NPCE cells with the human CB1 (hCB1) receptor, increased I Cl,Win , consistent with increased receptor expression, and I Cl,Win in hCB1 receptor-transfected cells was decreased after application of a CB1 receptor inverse agonist, SR 141716. 6 Constitutive activity for CB1 receptors was not significant in NPCE cells as transfection with hCB1 receptors did not increase basal Cl À current, nor was basal current inhibited by SR 141716. 7 I Cl,Win was inhibited by PTX preincubation, by transfection with ct-bARK and by the MEK inhibitor, PD98059, but unaffected by the PI3K inhibitor, wortmannin. 8 We conclude that both A3 and CB1 receptors activate a PKC-sensitive Cl À current in human NPCE cells via a G i/o /Gbg signaling pathway, in a manner independent of PI3K but involving MAPK.

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The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein

Cited by 92 publications

References 31 publications

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

Synaptic transmission at retinal ribbon synapses

A3 adenosine and CB1 receptors activate a PKC‐sensitive Cl⁻ current in human nonpigmented ciliary epithelial cells via a Gβγ‐coupled MAPK signaling pathway

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The human eye expresses high levels of CB1 cannabinoid receptor mRNA and protein

Cited by 92 publications

References 31 publications

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

Agonist‐dependent cannabinoid receptor signalling in human trabecular meshwork cells

Synaptic transmission at retinal ribbon synapses

A3 adenosine and CB1 receptors activate a PKC‐sensitive Cl− current in human nonpigmented ciliary epithelial cells via a Gβγ‐coupled MAPK signaling pathway

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A3 adenosine and CB1 receptors activate a PKC‐sensitive Cl⁻ current in human nonpigmented ciliary epithelial cells via a Gβγ‐coupled MAPK signaling pathway