Co‐activation of PKA and PKC in cerebrocortical nerve terminals synergistically facilitates glutamate release

Protein kinase A and protein kinase C are involved in processes that enhance glutamate release at glutamatergic nerve terminals. However, it is not known whether these two kinases co‐exist within the same nerve terminal, nor is it clear what impact their simultaneous activation may have on neurotransmitter release. In cerebrocortical nerve terminals, co‐application of forskolin, which increases cAMP levels and activates protein kinase A, and 4β‐phorbol dibutyrate, a direct activator of protein kinase C, synergistically enhanced the spontaneous release of glutamate. This enhancement exhibited both tetrodotoxin‐sensitive and tetrodotoxin‐resistant components. Interestingly, the tetrodotoxin‐resistant component of release was not observed when cyclic AMP‐dependent protein kinase (PKA) and calcium‐ and phospholipid‐dependent protein kinase (PKC) were activated separately, but developed slowly after the co‐activation of the two kinases, accounting for 50% of the facilitated release. This release component was dependent on voltage‐dependent Ca2+ channels that opened spontaneously after PKA and PKC activation and occurred in the absence of Na+ channel firing. These data provide functional evidence for the co‐existence of PKA‐ and PKC‐signalling pathways in a subpopulation of glutamatergic nerve terminals.

[1]  W. Catterall,et al.  Allosteric modulation of Ca2+ channels by G proteins, voltage-dependent facilitation, protein kinase C, and Cavβ subunits , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[2]  D. Nicholls,et al.  An Ion Channel Locus for the Protein Kinase C Potentiation of Transmitter Glutamate Release from Guinea Pig Cerebrocortical Synaptosomes , 1991, Journal of neurochemistry.

[3]  Kenneth M. Johnson,et al.  Mechanism of Action of rab3A in Mossy Fiber LTP , 1998, Neuron.

[4]  J. Sánchez-Prieto,et al.  Presynaptic Modulation of Glutamate Release Targets Different Calcium Channels in Rat Cerebrocortical Nerve Terminals , 1997, The European journal of neuroscience.

[5]  J. Waters,et al.  Phorbol Esters Potentiate Evoked and Spontaneous Release by Different Presynaptic Mechanisms , 2000, The Journal of Neuroscience.

[6]  R. Nicoll,et al.  Mediation of hippocampal mossy fiber long-term potentiation by cyclic AMP. , 1994, Science.

[7]  Paul Antoine Salin,et al.  Cyclic AMP Mediates a Presynaptic Form of LTP at Cerebellar Parallel Fiber Synapses , 1996, Neuron.

[8]  D. Johnston,et al.  Downregulation of Transient K+ Channels in Dendrites of Hippocampal CA1 Pyramidal Neurons by Activation of PKA and PKC , 1998, The Journal of Neuroscience.

[9]  C. Stevens,et al.  Regulation of the Readily Releasable Vesicle Pool by Protein Kinase C , 1998, Neuron.

[10]  W. Catterall,et al.  Cyclic AMP-dependent phosphorylation of the alpha subunit of the sodium channel in synaptic nerve ending particles. , 1984, The Journal of biological chemistry.

[11]  T. Abe.  [Calcium channels]. , 1997, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[12]  C F Stevens,et al.  Increased transmitter release at excitatory synapses produced by direct activation of adenylate cyclase in rat hippocampal slices , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  J. Storm,et al.  Interaction between alpha- and beta-adrenergic receptor agonists modulating the slow Ca(2+)-activated K+ current IAHP in hippocampal neurons. , 1996, The European journal of neuroscience.

[14]  R. S. Jones,et al.  Differential actions of PKA and PKC in the regulation of glutamate release by group III mGluRs in the entorhinal cortex. , 2001, Journal of neurophysiology.

[15]  P. Greengard,et al.  Phosphorylation and associated translocation of the 87-kDa protein, a major protein kinase C substrate, in isolated nerve terminals. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Robert C. Malenka,et al.  Potentiation of synaptic transmission in the hippocampus by phorbol esters , 1986, Nature.

[17]  A. Akaike,et al.  Cyclic AMP-dependent modulation of N- and Q-type Ca2+ channels expressed in Xenopus oocytes , 1996, Neuroscience Letters.

[18]  Xin-sheng Wu,et al.  Protein Kinase C Increases the Apparent Affinity of the Release Machinery to Ca 2 by Enhancing the Release Machinery Downstream of the Ca 2 Sensor , 2001 .

[19]  J. Sweatt,et al.  PKA Modulation of Kv4.2-Encoded A-Type Potassium Channels Requires Formation of a Supramolecular Complex , 2002, The Journal of Neuroscience.

[20]  K. Colby,et al.  Inhibition of voltage-gated K channels in synaptosomes by sn-1,2- dioctanoylglycerol, an activator of protein kinase C , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[21]  R. Shigemoto,et al.  Subtype-specific Expression of Group III Metabotropic Glutamate Receptors and Ca2+ Channels in Single Nerve Terminals* , 2002, The Journal of Biological Chemistry.

[22]  P. Conn,et al.  Presynaptic enhancement of excitatory synaptic transmission by beta-adrenergic receptor activation. , 1994, Journal of neurophysiology.

[23]  D. Nicholls,et al.  Protein kinase C and the regulation of glutamate exocytosis from cerebrocortical synaptosomes. , 1993, The Journal of biological chemistry.

[24]  T. Soong,et al.  Determinants of PKC-dependent modulation of a family of neuronal calcium channels , 1995, Neuron.

[25]  D. Terrian,et al.  Transduction of a protein kinase C‐generated signal into the long‐lasting facilitation of glutamate release , 1993, Hippocampus.

[26]  D. Nicholls,et al.  Repetitive Action Potentials in Isolated Nerve Terminals in the Presence of 4‐Aminopyridine: Effects on Cytosolic Free Ca2+ and Glutamate Release , 1989, Journal of neurochemistry.

[27]  Xin-sheng Wu,et al.  Protein Kinase C Increases the Apparent Affinity of the Release Machinery to Ca2+ by Enhancing the Release Machinery Downstream of the Ca2+ Sensor , 2001, The Journal of Neuroscience.

[28]  R. Zucker,et al.  Enhancement of synaptic transmission by cyclic AMP modulation of presynaptic Ih channels , 2000, Nature Neuroscience.

[29]  P. Castillo,et al.  Assessing the role of Ih channels in synaptic transmission and mossy fiber LTP , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[30]  A. Omori,et al.  Phosphorylation of 25-kDa Synaptosome-associated Protein , 1996, The Journal of Biological Chemistry.

[31]  J. Sánchez-Prieto,et al.  Two Components of Glutamate Exocytosis Differentially Affected by Presynaptic Modulation , 1996, Journal of neurochemistry.

[32]  Y. Takai,et al.  Presynaptic Mechanism for Phorbol Ester-Induced Synaptic Potentiation , 1999, The Journal of Neuroscience.

[33]  J. Rostas,et al.  A rapid method for isolation of synaptosomes on Percoll gradients , 1986, Brain Research.

[34]  R. Tsien,et al.  A new generation of Ca2+ indicators with greatly improved fluorescence properties. , 1985, The Journal of biological chemistry.

[35]  Scott M Thompson,et al.  Short‐term synaptic plasticity, simulation of nerve terminal dynamics, and the effects of protein kinase C activation in rat hippocampus , 2002, The Journal of physiology.

[36]  Ming Li,et al.  Convergent regulation of sodium channels by protein kinase C and cAMP-dependent protein kinase. , 1993, Science.

[37]  E. Kandel,et al.  Cyclic AMP induces functional presynaptic boutons in hippocampal CA3–CA1 neuronal cultures , 1999, Nature Neuroscience.

[38]  J. Sánchez-Prieto,et al.  cAMP-dependent Facilitation of Glutamate Release by β-Adrenergic Receptors in Cerebrocortical Nerve Terminals* , 1996, The Journal of Biological Chemistry.

[39]  D. Madison,et al.  Phorbol esters enhance synaptic transmission by a presynaptic, calcium‐dependent mechanism in rat hippocampus. , 1993, The Journal of physiology.

[40]  Y. H. Zhang,et al.  Phorbol ester-induced inhibition of potassium currents in rat sensory neurons requires voltage-dependent entry of calcium. , 2001, Journal of neurophysiology.

[41]  S. Dib-Hajj,et al.  NaN, a novel voltage-gated Na channel, is expressed preferentially in peripheral sensory neurons and down-regulated after axotomy. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  D. Lovinger,et al.  Protein kinase C modulates glutamate receptor inhibition of Ca2+ channels and synaptic transmission , 1993, Nature.

[43]  A. Ogura,et al.  Increase in number of functional release sites by cyclic AMP-dependent protein kinase in cultured neurons isolated from hippocampal dentate gyrus , 2001, Neuroscience Research.

[44]  D. Nicholls,et al.  Localized Ca2+ entry preferentially effects protein dephosphorylation, phosphorylation, and glutamate release. , 1992, The Journal of biological chemistry.

[45]  E Neher,et al.  Preferential potentiation of fast-releasing synaptic vesicles by cAMP at the calyx of Held. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[46]  O. Manzoni,et al.  Visualization of Cyclic AMP–Regulated Presynaptic Activity at Cerebellar Granule Cells , 1998, Neuron.

[47]  P. Haydon,et al.  Modulation of an early step in the secretory machinery in hippocampal nerve terminals. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Linda M Boland,et al.  Protein kinase C inhibits Kv1.1 potassium channel function. , 1999, American journal of physiology. Cell physiology.

[49]  T. Südhof,et al.  Phosphorylation of Munc-18/n-Sec1/rbSec1 by Protein Kinase C , 1996, The Journal of Biological Chemistry.

[50]  T. Südhof,et al.  Region-Specific Phosphorylation of Rabphilin in Mossy Fiber Nerve Terminals of the Hippocampus , 1998, The Journal of Neuroscience.

[51]  Uri Ashery,et al.  Phosphorylation of Snapin by PKA modulates its interaction with the SNARE complex , 2001, Nature Cell Biology.

[52]  I. Levitan,et al.  Modulation of calcium-activated potassium channels from rat brain by protein kinase A and phosphatase 2A , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[53]  R. Duvoisin,et al.  Cyclic AMP‐dependent protein kinase phosphorylates group III metabotropic glutamate receptors and inhibits their function as presynaptic receptors , 2001, Journal of neurochemistry.

[54]  P W Gean,et al.  Isoproterenol potentiates synaptic transmission primarily by enhancing presynaptic calcium influx via P- and/or Q-type calcium channels in the rat amygdala , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[55]  B. Strowbridge,et al.  Glutamate Receptors Mediate TTX-Resistant Synchronous Activity in the Rat Hippocampus , 1999, The Journal of Neuroscience.

[56]  D. Nicholls,et al.  Calcium‐Dependent and‐Independent Release of Glutamate from Synaptosomes Monitored by Continuous Fluorometry , 1987, Journal of neurochemistry.

[57]  R. Shigemoto,et al.  The Inhibition of Glutamate Release by Metabotropic Glutamate Receptor 7 Affects Both [Ca2+] c and cAMP , 2002, The Journal of Biological Chemistry.

[58]  J. Storm,et al.  Interaction Between α and β‐Adrenergic Receptor Agonists Modulating the Slow Ca2+‐activated K+ Current ‐ IAHP in Hippocampd Neurons , 1996 .