Opposing effects of phorbol esters on transmitter release and calcium currents at frog motor nerve endings

Redman, R. S.; Searl, Timothy J; Hirsh, Jody K.; Silinsky, Eugene M.

doi:10.1111/j.1469-7793.1997.041bo.x

Cited by 46 publications

(61 citation statements)

References 27 publications

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“…This view is supported by a number of studies in which pharmacological effects of phorbol esters and other PKC-directed drugs could not be correlated with PKC function (e.g. Scholfield and Smith, 1989;Fabbri et al, 1994;Simon et al, 1996;Redman et al, 1997;Stevens and Sullivan, 1998;Hori et al, 1999;Honda et al, 2000;Iwasaki et al, 2000;Waters and Smith, 2000). More recently, several studies provided direct evidence for the functional importance of the regulation of four non-PKC DAG/phorbol-ester receptors by DAG and phorbol esters in distinct cellular processes.…”

Section: Non-pkc C1 Domain Proteinssupporting

confidence: 48%

Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters

Brose

Rosenmund

2002

Journal of Cell Science

324

280

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Diacylglycerol is an essential second messenger in mammalian cells. The most prominent intracellular targets of diacylglycerol and of the functionally analogous phorbol esters belong to the protein kinase C (PKC) family. However,at least five alternative types of high-affinity diacylglycerol/phorbol-ester receptor are known: chimaerins, protein kinase D, RasGRPs, Munc13s and DAG kinase γ. Recent evidence indicates that these have functional roles in diacylglycerol second messenger signalling in vivo and that several cellular processes depend on these targets rather than protein kinase C isozymes. These findings contradict the still prevalent view according to which all diacylglycerol/phorbol-ester effects are caused by the activation of protein kinase C isozymes. RasGRP1 (in Ras/Raf/MEK/ERK signalling) and Munc13-1 (in neurotransmitter secretion) are examples of non-PKC diacylglycerol/phorbol-ester receptors that mediate diacylglycerol and phorbol-ester effects originally thought to be caused by PKC isozymes. In the future, pharmacological studies on PKC must be complemented with alternative experimental approaches to allow the separation of PKC-mediated effects from those caused by alternative targets of the diacylglycerol second messenger pathway. The examples of RasGRP1 and Munc13-1 show that detailed genetic analyses of C1-domain-containing non-PKC diacylglycerol/phorbol-ester receptors in mammals are ideally suited to achieve this goal.

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Section: Non-pkc C1 Domain Proteinssupporting

confidence: 48%

Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters

Brose

Rosenmund

2002

Journal of Cell Science

324

280

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“…However, in spite of relatively high concentrations, the blocking effect of PKC inhibitors was incomplete, implying that there may be an additional mechanism mediating the effect of phorbol ester. While an involvement of PKC in the PESP has been suspected (Scholfield and Smith, 1989;Redman et al, 1997), it was recently reported that phorbol esters or DAG stimulates the vesicular protein Doc2␣ to interact with the plasma membrane-associated protein Munc13-1 (Orita et al, 1997). The N-terminal domain (Mid) of Doc2␣ is involved in this interaction.…”

Section: Discussionmentioning

confidence: 99%

“…However, there is no direct evidence to indicate which, if any, of the above targets are involved in the phorbol ester-induced synaptic potentiation (PESP). Furthermore, an involvement of PKC in the PESP has been questioned recently at some synapses, where certain PKC inhibitors had no effect on the PESP (Redman et al, 1997). It has been reported that Munc13-1, a mammalian homolog of Caenorhabditis elegans unc13p, has a diacylglycerol (DAG) receptor similar in affinity to PKC and is localized in the plasma membrane near the release site (Betz et al, 1998).…”

Section: Abstract: Phorbol Ester; Synaptic Facilitation; Doc2␣; Muncmentioning

confidence: 99%

“…This presynaptic facilitatory effect of phorbol ester is thought to be mediated by protein kinase C (PKC) through (1) activation of calcium channels (Fossier et al, 1990;O'Dell and Alger, 1991;Parfitt and Madison, 1993;Swartz et al, 1993;Stea et al, 1995), (2) inhibition of potassium channels (Barban et al, 1985;Storm, 1987;Doerner et al, 1988;Hoffman and Johnston, 1998), or (3) activation of exocytotic machinery downstream of Ca 2ϩ influx (C apogna et al, 1995;Redman et al, 1997). However, there is no direct evidence to indicate which, if any, of the above targets are involved in the phorbol ester-induced synaptic potentiation (PESP).…”

Section: Abstract: Phorbol Ester; Synaptic Facilitation; Doc2␣; Muncmentioning

confidence: 99%

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Presynaptic Mechanism for Phorbol Ester-Induced Synaptic Potentiation

1999

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Phorbol ester facilitates transmitter release at a variety of synapses, and the phorbol ester-induced synaptic potentiation (PESP) is a model for presynaptic facilitation. To address the mechanism underlying PESP, we have made paired whole-cell recordings from the giant presynaptic terminal, the calyx of Held, and its postsynaptic target in the medial nucleus of the trapezoid body in rat brainstem slices. Phorbol ester potentiated EPSCs without affecting either presynaptic calcium currents or potassium currents. Protein kinase C inhibitors applied from outside or injected directly into the presynaptic terminal attenuated the PESP. Furthermore, presynaptic loading of a synthetic peptide with the sequence of the N-terminal domain of Doc2␣ interacting with Munc13-1 (Mid peptide) significantly attenuated PESP, whereas mutated Mid peptide had no effect. We conclude that the target of the presynaptic facilitatory effect of phorbol ester resides downstream of calcium influx and may involve both protein kinase C and Doc2␣ -Munc13-1 interaction.

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“…Addition of H-7 to the solution containing CCPA did not modify the effect of the A 1 analog on mepp frequency (55.671.9% of control values, n ¼ 4, Figure 4b). On the other hand, if stimulation of PKC is the reason for inactivation of Ltype VDCCs, 200 nM PMA, a phorbol ester known to activate PKC at neuromuscular junctions (Shapira et al, 1987;Redman et al, 1997;Angleson & Betz, 2001), would occlude…”

Section: Mechanism Of Action Of Ccpa On L-type Vdccsmentioning

confidence: 99%

Presynaptic inhibition of spontaneous acetylcholine release induced by adenosine at the mouse neuromuscular junction

Lorenzo

Veggetti

Muchnik

et al. 2004

British J Pharmacology

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1 At the mouse neuromuscular junction, adenosine (AD) and the A 1 agonist 2-chloro-N 6 -cyclopentyl-adenosine (CCPA) induce presynaptic inhibition of spontaneous acetylcholine (ACh) release by activation of A 1 AD receptors through a mechanism that is still unknown. To evaluate whether the inhibition is mediated by modulation of the voltage-dependent calcium channels (VDCCs) associated with tonic secretion (L-and N-type VDCCs), we measured the miniature endplate potential (mepp) frequency in mouse diaphragm muscles. 2 Blockade of VDCCs by Cd 2 þ prevented the effect of the CCPA. Nitrendipine (an L-type VDCC antagonist) but not o-conotoxin GVIA (an N-type VDCC antagonist) blocked the action of CCPA, suggesting that the decrease in spontaneous mepp frequency by CCPA is associated with an action on L-type VDCCs only. 3 As A 1 receptors are coupled to a G i/o protein, we investigated whether the inhibition of PKA or the activation of PKC is involved in the presynaptic inhibition mechanism. Neither N-(2[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide (H-89, a PKA inhibitor), nor 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine (H-7, a PKC antagonist), nor phorbol 12-myristate 13-acetate (PHA, a PKC activator) modified CCPA-induced presynaptic inhibition, suggesting that these second messenger pathways are not involved. 4 The effect of CCPA was eliminated by the calmodulin antagonist N-(6-aminohexil)-5-chloro-1-naphthalenesulfonamide hydrochloride (W-7) and by ethylene glycol-bis(b-aminoethyl ether)-N,N,N 0 ,N 0 -tetraacetic acid-acetoxymethyl ester e6TD-BM, which suggests that the action of CCPA to modulate L-type VDCCs may involve Ca 2 þ -calmodulin. 5 To investigate the action of CCPA on diverse degrees of nerve terminal depolarization, we studied its effect at different external K þ concentrations. The effect of CCPA on ACh secretion evoked by 10 mM K þ was prevented by the P/Q-type VDCC antagonist o-agatoxin IVA. 6 CCPA failed to inhibit the increases in mepp frequency evoked by 15 and 20 mM K þ . We demonstrated that, at high K þ concentrations, endogenous AD occupies A1 receptors, impairing the action of CCPA, since incubation with 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, an A 1 receptor antagonist) and adenosine deaminase (ADA), which degrades AD into the inactive metabolite inosine, increased mepp frequency compared with that obtained in 15 and 20 mM K þ in the absence of the drugs. Moreover, CCPA was able to induce presynaptic inhibition in the presence of ADA. It is concluded that, at high K þ concentrations, the activation of A 1 receptors by endogenous AD prevents excessive neurotransmitter release.

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Opposing effects of phorbol esters on transmitter release and calcium currents at frog motor nerve endings

Cited by 46 publications

References 27 publications

Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters

Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters

Presynaptic Mechanism for Phorbol Ester-Induced Synaptic Potentiation

Presynaptic inhibition of spontaneous acetylcholine release induced by adenosine at the mouse neuromuscular junction

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