Cell Calcium 38 (2005) 369–374

Calcium signaling and synaptic modulation: Regulation ofendocannabinoid-mediated synaptic modulation by calcium

Takako Ohno-Shosakua,b, Yuki Hashimotodania, Takashi Maejimaa,c, Masanobu Kanoa,∗a Department of Cellular Neurophysiology, Graduate School of Medical Science,

Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japanb Department of Impairment Study, Graduate Course of Rehabilitation Science, Division of Health Sciences,Graduate School of Medical Science, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan

c Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan

Received 20 June 2005; accepted 28 June 2005Available online 8 August 2005

Abstract

Postsynaptic Ca2+ signal influences synaptic transmission through multiple mechanisms. Some of them involve retrograde messengerst ynapticr ndocannabi-n utC e.T d byC or type 1( tedi he brain, byw n.©

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hat are released from postsynaptic neurons in a Ca2+-dependent manner and modulate transmitter release through activation of preseceptors. Recent studies have revealed essential roles of endocannabinoids in retrograde modulation of synaptic transmission. Eoid release is induced by either postsynaptic Ca2+ elevation alone or activation of postsynaptic Gq/11-coupled receptors with or withoa2+ elevation. The former pathway is independent of phospholipase C� (PLC�) and requires a large Ca2+ elevation to a micromolar ranghe latter pathway requires PLC� and is facilitated by a moderate Ca2+ elevation to a submicromolar range. This facilitation is causea2+-dependency of receptor-driven PLC� activation. The released endocannabinoids then activate presynaptic cannabinoid recept

CB1), and suppress transmitter release from presynaptic terminals. Both CB1 receptors and Gq/11-coupled receptors are widely distribun the brain. Thus, the endocannabinoid-mediated retrograde modulation may be an important and widespread mechanism in thich postsynaptic events including Gq/11-coupled receptor activation and Ca2+ elevation can retrogradely influence presynaptic functio2005 Elsevier Ltd. All rights reserved.

eywords:Calcium signaling; Gq/11-coupled receptor; Endocannabinoid; Phospholipase C�

. Introduction

In the nervous system, postsynaptic Ca2+ ions play impor-ant roles in the regulation of synaptic transmission[1].levation of postsynaptic Ca2+ concentration triggers sev-ral forms of short- and long-term synaptic modulations

hrough multiple mechanisms. The Ca2+ elevation can modu-ate functions of postsynaptic receptors through phosphoryla-ion/dephosphorylation processes[2–4]. The Ca2+ elevationan also induce a change in the number of surface receptorsn postsynaptic membrane through insertion/endocytosisrocesses[5,6]. In addition to these postsynaptic changes,

∗ Corresponding author. Tel.: +81 76 265 2170; fax: +81 76 234 4224.E-mail address:mkano@med.kanazawa-u.ac.jp (M. Kano).

presynatpic function can also be controlled by postsytic Ca2+ signal through retrograde messengers[7]. Endo-cannabinoids are the most widely accepted substancretrograde messengers in the brain. The production/reof endocannabioids are known to depend on Ca2+-signalingin postsynaptic neurons[7–12]. In this review, we focus othe roles of postsynaptic Ca2+ signaling in endocannabinoimediated retrograde modulation of presynaptic function

2. Cannabinoid receptors and endocannabinoids

Cannabinoid receptor type 1 (CB1) is one of the mabundant G protein-coupled seven-transmembrane-doreceptors in the brain. This receptor is located denon axons and axon terminals of certain types of n

143-4160/$ – see front matter © 2005 Elsevier Ltd. All rights reserved.oi:10.1016/j.ceca.2005.06.014

370 T. Ohno-Shosaku et al. / Cell Calcium 38 (2005) 369–374

rons [13,14]. The CB1-rich neurons include cholecys-tokinin (CCK)-positive basket cells in the hippocampus[15] and cortex[16], granule cells and inhibitory interneu-rons in the cerebellar cortex and medium-sizes spinyneurons in the striatum[14,17]. Several molecules areidentified as endogenous ligands for cannabinoid recep-tors (endocannabinoids)[10,18]. Two major endocannabi-noids are arachidonoylethanolamide (anandamide)[19] and2-arachidonoylglycerol (2-AG)[20,21]. Anandamide isbiosynthesized byN-acyltransferase and phospholipase D,whereas 2-AG is mainly produced by phospholipase C (PLC)and diacylglycerol (DAG) lipase[22–24]. These moleculesare synthesized in response to certain stimuli (describedbelow), and assumed to diffuse out across the cell membraneimmediately after their production. The endocannabinoidsreleased from postsynaptic neurons then activate presynapticCB1 receptors, and suppress transmitter release[7–12]. Inthe following sections, we describe the roles of postsynapticCa2+ signaling in generating endocannabinoids that mediateretrograde synaptic modulation.

3. Endocannabinoid release triggered bydepolarization-induced Ca2+ elevation

In various brain regions, it has been demonstrated thatp se eleastT sesia inhi-b ost-s s onc n-i andD ngers[ -lrrp int ngC im-i on-s ronst ri con-t LCi 67f mes-s alD X-2 edD easC , the

negative effect of FAAH inhibitor on DSI suggests that2-AG rather than anandamide is released during DSI. Ineither case, it is still unclear which enzyme is activated byCa2+.

4. Endocannabinoid release triggered by activationof Gq/11-coupled receptors

In addition to strong Ca2+ elevation, postsynatpic activa-tion of Gq/11-coupled receptors also causes endocannabinoid-mediated retrograde suppression without Ca2+ elevation[38–40]. This type of modulation was originally found incerebellar Purkinje cells[38]. In this study, application ofDHPG, an agonist of group I metabotropic glutamate recep-tors (mGluRs), induced suppression of excitatory transmis-sion from climbing fibers to Purkinje cells in cerebellar slices.By examining the mechanisms of this DHPG-induced sup-pression, it has been demonstrated that activation of groupI mGluRs on Purkinje cells induces release of endocannabi-noids, which retrogradely act on presynaptic CB1 receptorsand suppress glutamate release from climbing fiber terminals.Importantly, this mGluR-induced endocannabinoid releasedoes not require Ca2+ elevation in Purkinje cells[38]. Theendocannabinoid-mediated retrograde modulation triggeredby activation of group I mGluR was also found at hippocam-p ,a soc ressest ptors[ ec tt is 2-A

5o

geredbrr abi-n op-e beenr acili-t ofg -i asede ighert imulia cti-vb do-c endo-c

ostsynaptic depolarization-induced Ca2+ elevation causendocannabinoid release, and suppresses transmitter r

hrough activation of presynaptic CB1 receptors.[25–30].his phenomenon was originally found at inhibitory synap

n the cerebellum[31] and then in the hippocampus[32],nd was named depolarization-induced suppression ofition (DSI). Later, a similar phenomenon induced by pynaptic depolarization was found at excitatory synapseerebellar Purkinje cells[27], and was termed depolarizatio

nduced suppression of excitation (DSE). Both DSISE involve endocannabinoids as retrograde messe

25–30], and require a large Ca2+ elevation to a micromoar range[33,34]. Several studies estimated the Ca2+ levelequired for DSI/DSE induction. The estimated Ca2+ levelequired for DSI/DSE induction is∼4�M for hippocam-al DSI [34] and∼15�M for cerebellar DSI/DSE to atta

he half-maximal effect[33]. Since DSI/DSE requires stroa2+ elevation, its physiological significance might be l

ted. In fact, a study on hippocampal slices has demtrated that normal firing patterns of hippocampal neuhat occur in vivo do not elicit DSI[35]. The moleculadentity of endocannabinoids that mediate DSI/DSE isroversial. In a study on hippocampal DSI, both the Pnhibitor U73122 and the DAG lipase inhibitor RHC-802ailed to suppress DSI, suggesting that the retrogradeenger is not 2-AG[36]. Another study on hippocampSI showed that inhibition of cyclooxygenase-2 (CO), but not fatty acid amide hydrolase (FAAH), prolongSI [37]. FAAH mainly degrades anandamide, wherOX-2 can degrade both 2-AG and anandamide. Thus

eal inhibitory synapses[39,40]. Similar to group I mGluRsctivation of postsynatpic M1/M3 muscarinic receptors alauses endocannabinoid release and retrogradely suppransmitter release by activating presynaptic CB1 rece41]. Since both group I mGluRs and M1/M3 receptors aroupled to PLC through Gq/11 proteins, it is most likely thahe molecule that mediates these forms of suppressionG rather than anandamide.

. Endocannabinoid release triggered by activationf Gq/11-coupled receptors and Ca2+ elevation

As described above, endocannabinoid release is trigy either strong Ca2+ elevation or activation of Gq/11-coupledeceptors such as group I mGluRs and M1/M3 muscariniceceptors. Although these two stimuli can drive endocannoid signaling independently, they can also work in a corative manner to produce endocannabinoids. It haseported that the endocannabinoid release is markedly fated when Ca2+ elevation is combined with the activationroup I mGluRs or M1/M3 receptors[39,42,43]. In our stud

es on cultured hippocampal neurons, the amount of relendocannabinoids is estimated to be several times h

han the simple sum of the amounts induced by each stlone[39,42]. It should be noted that weak receptor aation by a low dose of agonist and small Ca2+ elevationy a short depolarization, both of which do not induce enannabinoid release when applied separately, can driveannabinoid signaling when applied simultaneously[39,42].

T. Ohno-Shosaku et al. / Cell Calcium 38 (2005) 369–374 371

Fig. 1. Receptor-driven endocannabinoid release is dependent on intracel-lular Ca2+ concentration. (A) Cannabinoid-sensitive inhibitory postsynapticcurrents (IPSCs) were recorded from rat cultured hippocampal neurons dia-lyzed with various pCa solutions. Application of the muscarinic agonistoxotremorine-M (oxo-M) suppressed IPSCs in a Ca2+-dependent manner.(B) Averaged data for oxo-M-induced suppression of IPSCs at three differentpCa levels. (Modified from[50].).

Thus, it is expected that some mechanisms must exist todetect the coincidence of the two stimuli for endocannabi-noid release.

It is known that Gq/11-coupled receptors including groupI mGluRs and M1/M3 receptors[44,45] activate PLC�,one of the five types (�, �, �, � and �) of PLC. It isalso known that all of the five types of PLC require Ca2+

for their catalytic function, although Ca2+ concentrationrequired for maximum activation is different in different PLCisozymes[44,46–49]. Thus, if PLC� activation is requiredfor endocannabinoid production and sensitive to Ca2+ eleva-tion in a physiological range, PLC� can work as a codinci-dence detector for triggering endocannabinoid generation.We have recently tested this possibility[50]. By measur-ing cannabinoid-sensitive synaptic currents, we have foundthat the receptor-driven endocannabinoid release is depen-dent on physiological levels of intracellular Ca2+ concen-tration (Fig. 1) and is markedly enhanced by depolarization-induced Ca2+ elevation. By using exogenous TRPC6 channelas a biosensor for the PLC product diacylglycerol, we havedemonstrated that the receptor-driven PLC activation exhibitsa similar Ca2+-dependence to that of endocannabinoid release(Fig. 2). Neither endocannabinoid release nor PLC activa-tion was induced by receptor activation in PLC�1-knockoutmice. From these results, we conclude that PLC�1 servesas a coincidence detector through its Ca2+-dependency fort rons.I trongC tm eP ease[

Fig. 2. Receptor-driven PLC� activation is dependent on intracellular Ca2+

concentration. (A) Rat cultured hippocampal neurons expressing TRPC6channels were dialyzed with various pCa solutions. Application of oxo-Minduced an inward TRPC6 current, which reflects PLC� activity, in a Ca2+-dependent manner. (B) Averaged data for oxo-M-induced TRPC6 current atfour different pCa levels. (Modified from[50].).

6. Current models of endocannabinoid-mediatedretrograde modulation

Fig. 3 shows current models for the mechanisms ofendocannabinoid-mediated retrograde modulation. Postsy-naptic depolarization triggers Ca2+ influx by activatingvoltage-gated Ca2+ channels, and causes transient elevationof intracellular Ca2+ concentration. When Ca2+ concentra-tion is elevated to a micromolar range, endocannabinoidscan be produced through PLC�-independent pathway andare released from postsynaptic neurons (Fig. 3A). Activa-tion of Gq/11-coupled receptors such as group I mGluRs andM1/M3 muscarinic receptors stimulates PLC�, and causes 2-AG production through DAG lipase activity (Fig. 3B). ThisPLC�-dependent endocannabinoid release is markedly facil-itated by Ca2+ elevation because of the Ca2+-dependency ofPLC� (Fig. 3B). When receptors are strongly activated bya high dose of agonist, the endocannabinoid release can beinduced even at a resting level of Ca2+ concentration. Whenreceptors are activated weakly by a low dose of agonist, theendocannabinoid release is not induced at a resting Ca2+ level,but can be induced effectively when combined with Ca2+

elevation. The Ca2+ level required for this effect is a submi-cromolar range. This Ca2+-assisted drive of PLC�-dependentpathway seems of physiological significance. Through thispathway, mild receptor activation combined with small Ca2+

e icalc ively.T bindt mi-n ptora luta-m a

riggering endocannabinoid release in hippocampal neun contrast, the endocannabinoid-release induced by sa2+ elevation alone was intact in the PLC�1-knockououse, indicating that strong Ca2+ elevation can drivLC�1-independent pathway for endocannabinoid rel

50].

levation, both of which appear to occur under physiologonditions, can trigger endocannabinoid release effecthe released endocannabinoids diffuse retrogradely and

o CB1 receptor on excitatory or inhibitory presynaptic terals. The binding of endocannabinoids to the CB1 recectivates Gi/o proteins and suppresses the release of gate or GABA, presumably by inhibiting voltage-gated C2+

372 T. Ohno-Shosaku et al. / Cell Calcium 38 (2005) 369–374

Fig. 3. Current models of endocannabinoid-mediated retrograde suppres-sion of central synapses. (A) Strong postsynaptic depolarization inducesendocannabinoid production through PLC�-independent pathway. Thispathway requires elevation of intracellular Ca2+ concentration to a micro-molar range. (B) Postsynaptic activation of Gq/11-coupled receptors inducesthe production of endocannabinoid, presumably 2-AG, through PLC�-dependent pathway. This pathway is facilitated by mild Ca2+ elevation toa submicromolar range.

channels[51,52], activating K+ channels[52,53]or inhibitingrelease machinery directly[54].

7. Involvement of endocannabinoids in induction oflong-term synaptic plasticity

Several recent studies have reported that the endocannabinoid signal is required for long-term synaptic plasticity. Inthe striatum, high-frequency stimulation of the input fromthe cortex leads to long-term depression (LTD) of excitatorytransmission[55]. This striatal LTD was blocked by the CB1antagonist SR141716A, and was absent in CB1-deficientmice[56]. Examination of the effects of SR141716A appli-cation at various time points suggests that CB1 activation isnecessary for LTD induction but not for LTD maintenance[57]. A similar CB1-dependent LTD of excitatory transmis-sion has been reported in the nucleus accumbens[58]. CB1-dependent LTD of inhibitory transmission, which is inducedby low-or high-frequency stimulation, has been reported inthe basolateral amygdala[59] and the hippocampus[36].These studies demonstrated that LTD of inhibitory transmis-

sion (I-LTD) was blocked by CB1 antagonists and was absentin CB1-deficient mice[36,59]. The hippocampal I-LTD wasblokded by group I mGluR antagonists, the PLC inhibitorU73122, and the DAG lipase inhibitor RHC-80267, suggest-ing that 2-AG is produced during LTD induction throughgroup I mGluR-Gq/11-PLC pathway and DAG lipase[36].These findings suggest that endocannabinoids are involvedin certain forms of long-term synaptic plasticity as well asshort-term synaptic modulation. Presynaptic mechanisms ofthese forms of synaptic plasticity remain to be elucidated.

8. Physiological significance of receptor-Gq/11-PLC�pathway in synaptic modulation

The receptor-Gq/11-PLC� signaling pathway is requiredfor endocannabinoid generation, especially under physiolog-ical conditions. This pathway is also involved in multipleintracellular signaling pathways other than endocannabinoidgeneration. The PLC� product IP3 drives Ca2+ mobilizationfrom internal stores through IP3 receptors. The other PLC�product DAG activates protein kinase C (PKC) and playsimportant roles in short- and long-term synaptic modulations[60,61]. All these signaling pathways are under the control ofthe extent of Gq/11-coupled receptor activation and intracel-l red dingn t ther ofaa

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ular Ca2+ level. Various types of Gq/11-coupled receptors aistributed in the brain, and are activated by the corresponeurotransmitters or modulators. It is therefore likely thaeceptor-Gq/11-PLC� pathway contributes to various formsctivity-dependent synaptic modulation through Ca2+, PKCnd endocannabinoids.

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