regulation of calcium channels by g protein-coupled receptors enzymes excitation- contraction gene...
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Regulation of Calcium Channels by G Protein-Coupled Receptors
Em
extracellular modulators
intracellular modulators
+
+
+
Ca2+
enzymesexcitation-contraction
genetranscription
membranepotential
exocytosis
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GABA NE
Transmitters decrease the calcium componentof sensory neurone action potentials
Dunlap K, Fischbach GD. Neurotransmitters decrease the calcium component of sensory neurone action potentials. Nature. 1978 Dec;276(5690):837-839.
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Calcium channels are multimeric proteins
S1 S2 S3
S4S5S6
+++++
S
SSS
Strock J, Diverse-Pierluissi MA. Ca2+ channels as integrators of G protein-mediated signaling in neurons. Mol Pharmacol. 2004 Nov;66(5):1071-1076. Epub 2004 Jul 21.
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Cav1.1 L a1S DHP Skeletal muscle Excitation-contraction, Gene regulation
Cav1.2 L a1C DHP Heart, endo., neurons Excitation-contraction, Hormone secretion
Cav1.3 L a1D DHP Endocrine cells and neurons Hormone secretion, Gene regulation
Cav1.4 L a1F Retina Tonic transmitter release
Cav2.1 P/Q a1A -Ag Neurons Exocytosis
Cav2.2 N a1B -Con Neurons Exocytosis
Cav2.3 R a1E SNX482 Neurons Exocytosis
Name Previous Alpha 1 Blocker Localization Function Name
Classification of high-voltage activated calcium channels
Strock J, Diverse-Pierluissi MA. Ca2+ channels as integrators of G protein-mediated signaling in neurons. Mol Pharmacol. 2004 Nov;66(5):1071-1076. Epub 2004 Jul 21.
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Active zones contain calcium channels and synaptic vesicles that interact with adaptor proteins
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Multiple G protein-mediated pathways inhibit voltage-dependent calcium channels
Strock J, Diverse-Pierluissi MA. Ca2+ channels as integrators of G protein-mediated signaling in neurons. Mol Pharmacol. 2004 Nov;66(5):1071-1076. Epub 2004 Jul 21.
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IVI II III
N-terminus loop I-II
loop II-III: synprint (aa-726-984)
loop II-III: remainder (985-1170)
C-terminus (aa 1916-2375)
Cytoplasmic domains of the alpha 1 subunit of the calcium channel
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IVI II III
181
MuncMint-1
SNAP25
synap.
syntaxin
Proteins that interact with the cytoplasmic domains of the alpha 1 subunit of the calcium
channel can interact with each other
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Proteins that interact with the cytoplasmic domains of the alpha 1 subunit of the calcium channel
Strock J, Diverse-Pierluissi MA. Ca2+ channels as integrators of G protein-mediated signaling in neurons. Mol Pharmacol. 2004 Nov;66(5):1071-1076. Epub 2004 Jul 21.
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*
Inhibition of N type calcium current has two components
200 pA
10 ms
*NE
CON*
*-80 mV
+80 mV
0 mV
* prepulse to +80mV
*
**
voltage-dependent voltage-independent
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Interaction of Gwith the calcium channel mediates transmitter-induced voltage-
dependent inhibition of calcium current
Jarvis SE, Zamponi GW. Interactions between presynaptic Ca2+ channels, cytoplasmic messengers and proteins of the synaptic vesicle release complex. Trends Pharmacol Sci. 2001 Oct;22(10):519-525.
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Binding of Gto the calcium channel displaces the beta subunit of the calcium channel
Zamponi GW, Snutch TP. Modulation of voltage-dependent calcium channels by G proteins.Curr Opin Neurobiol. 1998 Jun;8(3):351-356.
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Interaction of Gwith the calcium channel induces the “reluctant” state
Zamponi GW, Snutch TP. Modulation of voltage-dependent calcium channels by G proteins.Curr Opin Neurobiol. 1998 Jun;8(3):351-356.
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Cross-talk beween Gand protein kinase C in the modulation of calcium current
Cooper CB, Arnot MI, Feng ZP, Jarvis SE, Hamid J, Zamponi GW. Cross-talk between G-protein and protein kinase C modulation of N-type calcium channels is dependent on the G-protein beta subunit isoform. J Biol Chem. 2000 Dec;275(52):40777-40781.
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Cross-talk beween Gand protein kinase C in the modulation of calcium current is dependent on the type
of G
Cooper CB, Arnot MI, Feng ZP, Jarvis SE, Hamid J, Zamponi GW. Cross-talk between G-protein and protein kinase C modulation of N-type calcium channels is dependent on the G-protein beta subunit isoform. J Biol Chem. 2000 Dec;275(52):40777-40781.
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Dual regulation of voltage-gated calcium channels by PtdIns (4,5)P2
Wu L, Bauer CS, Zhen XG, Xie C, Yang J. Nature. 2002 Oct;419(6910):947-952.
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Stabilization of P/Q calcium current by PIP2
Tail current can be used to measure functional channels
PIP2 slowed down rundown after patch excision
Mg-ATP slowed down rundown after patch excision
Wu L, Bauer CS, Zhen XG, Xie C, Yang J. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2.Nature. 2002 Oct;419(6910):947-952.
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PtdIns (4,5)P2 induced voltage-dependent inhibition
Wu L, Bauer CS, Zhen XG, Xie C, Yang J. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2.Nature. 2002 Oct;419(6910):947-952.
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Receptor-mediated PIP2 hydrolysis: LHRH in frog sympathetic neurons
Inhibition is voltage-independent
Inhibition of PLC of U732122
Wu L, Bauer CS, Zhen XG, Xie C, Yang J. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2.Nature. 2002 Oct;419(6910):947-952.
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Multiple G protein coupled receptors mediate the inhibition of neuronal calcium channels
Strock J, Diverse-Pierluissi MA. Ca2+ channels as integrators of G protein-mediated signaling in neurons. Mol Pharmacol. 2004 Nov;66(5):1071-1076. Epub 2004 Jul 21.
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Cav2.2 channel
synaptotagmin (v-SNARE)
SNAP-25v
syntaxin
Cav2.2 channel
SNAP-25
syntaxin X
v
“willing”
“reluctant”
Binding of SNARE proteins to neuronal calcium channels
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Muth JN, Varadi G, Schwartz A. Use of transgenic mice to study voltage-dependent Ca2+ channels. Trends Pharmacol Sci. 2001 Oct;22(10):526-532.
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Muth JN, Varadi G, Schwartz A. Use of transgenic mice to
study voltage-dependent Ca2+ channels.
Trends Pharmacol Sci. 2001 Oct;22(10):526-532.
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Diverse-Pierluissi M, Remmers AE, Neubig RR, Dunlap K. Novel form of crosstalk between G protein and tyrosine kinase pathways. Proc Natl Acad Sci U S A. 1997 May 13;94(10):5417-21.
Time course of GABA-B receptor-mediated inhibition of N type current
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PI3K promotes voltage dependent calcium channel trafficking in the
plasma membrane
Viard P, Butcher AJ, Halet G, Davies A, Nurnberg B, Heblich F, Dolphin AC. Nat Neurosci. 2004
Sep;7(9):939-946.
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Effect of PI3K-induced production of PIP3 on Cav1.2/2a currents
Viard P, Butcher AJ, Halet G, Davies A, Nurnberg B, Heblich F, Dolphin AC. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nat Neurosci. 2004 Sep;7(9):939-946.
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Effect of PI3K on Calcium Channel Membrane Localization
Viard P, Butcher AJ, Halet G, Davies A, Nurnberg B, Heblich F, Dolphin AC. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nat Neurosci. 2004 Sep;7(9):939-946.
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Effect of S574A mutation on the PI3K and myr-Akt/PKB-induced regulation of Cav2.2
channels
Viard P, Butcher AJ, Halet G, Davies A, Nurnberg B, Heblich F, Dolphin AC. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nat Neurosci. 2004 Sep;7(9):939-946.