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doi: 10.1242/10.1242/jcs.00122

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

¹ Abteilung Molekulare Neurobiologie, Max-Planck-Institut für Experimentelle Medizin, D-37075 Göttingen, Germany
² Abteilung Membranbiophysik, Max-Planck-Institut für Biophysikalische Chemie, D-37077 Göttingen, Germany

View larger version (17K): [in a new window]   Fig. 1. C1-domain proteins that bind DAG and phorbol esters with high affinity. C1, protein kinase C conserved region 1; C2, protein kinase C conserved region 2 (CalB); DAG, diacylglycerol; DAGKa, diacylglycerol kinase accessory domain; DAGKc, diacylglycerol kinase catalytic domain; EF, EF hand; GAP, GTPase-activator protein; GEF, guanine nucleotide exchange factor; GRP, guanyl-releasing protein; PH, pleckstrin-homology domain; pKc, protein kinase C terminal domain; PKC, protein kinase C; PKD, protein kinase D; RasGEF, guanine nucleotide exchange factor for Ras-like small GTPases; RasGEFN, guanine nucleotide exchange factor for Ras-like GTPases (N-terminal motif); RhoGAP, GTPase-activator protein for Rho-like GTPases; S/T-Kc, serine/threonine protein kinases, catalytic domain; SH2, Src homology 2 domain.

View larger version (24K): [in a new window]   Fig. 2. Nonspecific effects of a bisindolylmaleimide-derived PKC inhibitor in hippocampal neurons. (A) Time course of phorbol-ester effects on evoked EPSCs in wildtype neurons (n=6). Application of PDBU (1 µM) is indicated by the white box. (B) Preincubation with 3 µM bisindoylmaleimide I (Gö6857, grey box) led to a partially irreversible rundown of evoked EPSC amplitudes but did not block the potentiation induced by application of 1 µM PDBU (white box). (C) Average evoked EPSC amplitudes in untreated neurons before and after bisindoylmaleimide I (3 µM) pretreatment (n=6). (D) Average phorbol-ester-dependent potentiation of evoked EPSC amplitudes (30 seconds following onset of application of 1 µM PDBU, n=6) in untreated and bisindoylmaleimide I (3 µM) pretreated neurons from experiments shown in (B). Error bars indicate s.e.m.

View larger version (16K): [in a new window]   Fig. 3. Neurons expressing a phorbol-ester-binding-deficient Munc13-1 are completely insensitive to phorbol esters. Time course of phorbol-ester effects on evoked EPSCs in hippocampal neurons from wild-type-like Munc13-2-deficient mice (black squares, n=6) and Munc13-2-deficient/Munc13-1H567K double mutant mice (grey circles, n=6). Application of PDBU (1 µM) is indicated by the black bar. EPSCs were evoked at 0.2 Hz and normalised to the initial amplitude. Error bars indicate s.e.m.

View larger version (26K): [in a new window]   Fig. 4. Model of Munc13-1 activation by DAG. See text for details. Note that only one mechanism of DAG synthesis (i.e. PI-PLCß) is depicted here. Other PI-PLC activities are likely to also activate Munc13s. Indeed, PI-PLC may be responsible for activation of Munc13-1 during high-frequency stimulation and intrasynaptic accumulation of Ca2+.