cAMP-dependent protein kinase 1


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PKA and receptors, channels and pumps

The ability of cAMP-dependent protein kinase (PKA) to phosphorylate type I, II, and III inositol 1,4,5-trisphosphate (InsP3) receptors was examined. The receptors either were immunopurified from cell lines and then phosphorylated with purified PKA or were phosphorylated in intact cells after activating intracellular cAMP formation. The type I receptor is a good substrate for PKA, whereas type II and III receptors are phosphorylated relatively weakly. Despite these differences, each of the receptors is phosphorylated in intact cells in response to forskolin or activation of neurohormone receptors. Detailed examination of SH-SY5Y neuroblastoma cells, which express type I receptor, reveal that minor increases in cAMP concentration are sufficient to cause maximal phosphorylation. Thus, VIP and pituitary adenylyl cyclase activating peptide (acting through Gs-coupled pituitary adenylyl cyclase activating peptide-I receptors) are potent stimuli of type I receptor phosphorylation, and remarkably, even slight increases in cAMP concentration induced by carbachol (acting through Gq-coupled muscarinic receptors) or other Ca2+ mobilizing agents are sufficient to cause phosphorylation. Finally, PKA enhances InsP3-induced Ca2+ mobilization in a range of permeabilized cell types, irrespective of whether the type I, II, or III receptor is predominant. In summary, these data show that all InsP3 receptors are phosphorylated by PKA, albeit with marked differences in stoichiometry. The ability of both Gs- and Gq-coupled cell surface receptors to effect InsP3 receptor phosphorylation by PKA suggests that this process is widespread in mammalian cells and provides multiple routes by which the cAMP signaling pathway can influence Ca2+ mobilization (Wojcikiewicz, 1998).

Cyclic nucleotide-regulated phosphorylation of the neuronal type I inositol 1,4,5-trisphosphate (IP3) receptor immunopurified from rat cerebellar membranes was examined in vitro and in rat cerebellar slices in situ. The isolated IP3 receptor protein is phosphorylated by both cAMP- and cGMP-dependent protein kinases on two distinct sites as determined by thermolytic phosphopeptide mapping, phosphopeptide 1, representing Ser-1589, and phosphopeptide 2, representing Ser-1756 in the rat protein. Phosphopeptide maps show that cAMP-dependent protein kinase (PKA) labels both sites with the same time course and same stoichiometry, whereas cGMP-dependent protein kinase (PKG) phosphorylates Ser-1756 with a higher velocity and a higher stoichiometry than Ser-1589. Synthetic decapeptides corresponding to the two phosphorylation sites [peptide 1, AARRDSVLAA (Ser-1589), and peptide 2, SGRRESLTSF (Ser-1756)] were used to determine kinetic constants for the phosphorylation by PKG and PKA, and the catalytic efficiencies were in agreement with the results obtained by in vitro phosphorylation of the intact protein. In cerebellar slices prelabeled with [32P]orthophosphate, activation of endogenous kinases by incubation in the presence of cAMP/cGMP analogs and specific inhibitors of PKG and PKA induces in both cases a 3-fold increase in phosphorylation of the IP3 receptor. Thermolytic phosphopeptide mapping of in situ labeled IP3 receptor by PKA shows labeling on the same sites (Ser-1589 and Ser-1756) as in vitro. In contrast to the findings in vitro, PKG preferentially phosphorylates Ser-1589 in situ. Because both PKG and the IP3 receptor are specifically enriched in cerebellar Purkinje cells, PKG may be an important IP3 receptor regulator in vivo (Haug, 1999).

The two-electrode voltage-clamp and patch-clamp techniques have been used to study the effects of forskolin and cAMP on the ROMK1 channels, which are believed to be the native K+ secretory channels in the kidney. Addition of 1 microM forskolin or 100 microM 8-bromo-cAMP, within 10 min, has no significant effect on the current of ROMK1 channels expressed in Xenopus oocytes. In contrast, application of 1 microM forskolin, within 3 min, significantly increases whole-cell K+ current by 35%, when ROMK1 channels were coexpressed with the A kinase anchoring protein AKAP79, which was cloned from neuronal tissue. Two lines of evidence indicate that the effect of forskolin is mediated by a cAMP-dependent pathway: (1) addition of 100 microM 8-bromo-cAMP mimics the effect of forskolin, and (2) the effect of forskolin and cAMP is not additive. That AKAP is required for the effect of cAMP is further supported by experiments in which addition of ATP (100 microM) and cAMP (100 microM) restore the activity of run-down ROMK1 channels in inside-out patches in oocytes that coexpress ROMK1 and AKAP79 but not in those that express ROMK1 alone. Moreover, when RII, the regulatory subunit of type II protein kinase A, was used in an overlay assay, a RII-binding protein was identified in membranes obtained from the kidney cortex but not in membranes from oocytes. This suggests that the insensitivity of ROMK1 channels to forskolin and cAMP is due to the absence of AKAPs. It is concluded that AKAP may be a critical component that mediates the effect of protein kinase A on the ROMK channels in the kidney (Ali, 1998).

Molecular mechanisms that regulate in situ activation of ryanodine receptors (RY) in different cells are poorly understood. Caffeine (10 mM) releases Ca2+ from the endoplasmic reticulum (ER) in the form of small spikes in only 14% of cultured fura-2 loaded beta cells from ob/ob mice. Surprisingly, when forskolin, an activator of adenylyl cyclase is present, caffeine induces larger Ca2+ spikes in as many as 60% of the cells. Either forskolin or the phosphodiesterase-resistant PKA activator Sp-cAMPS alone does not release Ca2+ from ER. 4-Chloro-3-ethylphenol (4-CEP), an agent that activates RYs in other cell systems, releases Ca2+ from ER, giving rise to a slow and small increase in [Ca2+]i in beta cells. Prior exposure of cells to forskolin or caffeine (5 mM) qualitatively alters Ca2+ release by 4-CEP, giving rise to Ca2+ spikes. In glucose-stimulated beta cells forskolin induces Ca2+ spikes that are enhanced by 3,9-dimethylxanthine, an activator of RYs. Analysis of RNA from islets and insulin-secreting betaTC-3-cells by RNase protection assay, using type-specific RY probes, reveals low-level expression of mRNA for the type 2 isoform of the receptor (RY2). It is concluded that in situ activation of RY2 in beta cells requires cAMP-dependent phosphorylation, a process that recruits the receptor in a functionally operative form (Islam, 1998).

The ryanodine receptor (RyR)/calcium release channel on the sarcoplasmic reticulum (SR) is the major source of calcium (Ca2+) required for cardiac muscle excitation-contraction (EC) coupling. The channel is a tetramer comprised of four type 2 RyR polypeptides (RyR2) and four FK506 binding proteins (FKBP12.6). Protein kinase A (PKA) phosphorylation of RyR2 dissociates FKBP12.6 and regulates the channel open probability (Po). Using cosedimentation and coimmunoprecipitation, a macromolecular complex has been defined comprised of RyR2, FKBP12.6, PKA, the protein phosphatases PP1 and PP2A, and an anchoring protein, mAKAP. In failing human hearts, RyR2 is PKA hyperphosphorylated, resulting in defective channel function due to increased sensitivity to Ca2+-induced activation (Marx, 2000).

The interaction of intracellular free calcium ([Ca2+]i) and cAMP signaling mechanisms was examined in intact single megakaryocytes by using a combination of single-cell fluorescence microscopy to measure [Ca2+]i and flash photolysis of caged Ca2+, inositol 1,4, 5-trisphosphate (IP3), and/or cAMP in order to rapidly elevate the concentration of these compounds inside the cell. Photolysis of caged IP3 stimulates Ca2+ release from an IP3-sensitive store. The cAMP-elevating agent carbacyclin inhibits this IP3-induced rise in [Ca2+]i but does not affect the rate of Ca2+ removal from the cytoplasm after photolysis of caged Ca2+. Photolysis of caged cAMP during ADP-induced [Ca2+]i oscillations causes the [Ca2+]i oscillation to transiently cease without affecting the rate of Ca2+ uptake and/or extrusion. It has been concluded that the principal mechanism of cAMP-dependent inhibition of Ca2+ mobilization in megakaryocytes appears to be inhibition of IP3-induced Ca2+ release and not stimulation of Ca2+ removal from the cytoplasm. Two inhibitors of cAMP-dependent protein kinase, a specific peptide inhibitor of the catalytic subunit of cAMP protein kinase and KT5720, block the inhibitory effect of carbacyclin, indicating that the inhibition of IP3-induced Ca2+-release by carbacyclin is mediated by cAMP-dependent protein kinase. These results imply that cAMP protein kinase is required for inhibition of IP3-induced Ca2+-release, although it is not clear whether this inhibition requires phosphorylation of only the IP3 receptor (See Drosophila IP3R), or if the phosphorylation of other proteins is involved (Tertyshnikova, 1998).

A high density of transient A-type K+ channels is located in the distal dendrites of CA1 hippocampal pyramidal neurons and these channels shape EPSPs, limit the back-propagation of action potentials, and prevent dendritic action potential initiation. Because of the importance of these channels in dendritic signal propagation, their modulation by protein kinases would be of significant interest. The effects of activators of cAMP-dependent protein kinase (PKA) and the Ca2+-dependent phospholipid-sensitive protein kinase (PKC) were investigated on K+ channels in cell-attached patches from the distal dendrites of hippocampal CA1 pyramidal neurons. Inclusion of the membrane-permeant PKA activators 8-bromo-cAMP (8-br-cAMP) or forskolin in the dendritic patch pipette results in a depolarizing shift in the activation curve for the transient channels of approximately 15 mV. Activation of PKC by either of two phorbol esters also results in a 15 mV depolarizing shift of the activation curve. Neither PKA nor PKC activation affects the sustained or slowly inactivating component of the total outward current. This downregulation of transient K+ channels in the distal dendrites may be responsible for some of the frequently reported increases in cell excitability found after PKA and PKC activation. In support of this hypothesis, it was found that activation of either PKA or PKC significantly increased the amplitude of back-propagating action potentials in distal dendrites (Hoffman, 1998).

A Ca2+-pump ATPase, similar to that in the endoplasmic reticulum, has been located on the outer membrane of rat liver nuclei. The effect of cAMP-dependent protein kinase (PKA) on nuclear Ca2+-ATPase (NCA) was studied by using purified rat liver nuclei. Treatment of isolated nuclei with the catalytic unit of PKA results in the phosphorylation of a 105-kDa band that is recognized by antibodies specific for sarcoplasmic reticulum Ca2+-ATPase type 2b. Partial purification and immunoblotting confirm that the 105-kDa protein band phosphorylated by PKA is NCA. Measurement of ATP-dependent 45Ca2+ uptake into purified nuclei shows that PKA phosphorylation enhances the Ca2+-pumping activity of NCA. PKA phosphorylation of Ca2+-ATPase enhances the transport of 10-kDa fluorescent-labeled dextrans across the nuclear envelope. These are consistent with the notion that the crosstalk between the cAMP/PKA- and Ca2+-dependent signaling pathways identified at the cytoplasmic level extends to the nucleus. Furthermore, these data support a function for crosstalk in the regulation of calcium-dependent transport across the nuclear envelope (Rogue, 1998).

Several protein kinases are known to phosphorylate Ser/Thr residues of certain GABAA receptor subunits, yet the effect of phosphorylation on GABAA receptor function in neurons remains controversial, and the functional consequences of phosphorylating synaptic GABAA receptors of adult CNS neurons are poorly understood. Whole-cell patch-clamp recordings of GABAA receptor-mediated miniature IPSCs (mIPSCs) in CA1 pyramidal neurons and dentate gyrus granule cells (GCs) of adult rat hippocampal slices were used to determine the effects of cAMP-dependent protein kinase (PKA) and Ca2+/phospholipid-dependent protein kinase (PKC) activation on the function of synaptic GABAA receptors. The mIPSCs recorded in CA1 pyramidal cells and in GCs are differentially affected by PKA and PKC. In pyramidal cells, PKA reduces mIPSC amplitudes and enhances the fraction of events decaying with a double exponential, whereas PKC has no effect. In contrast, in GCs PKA is ineffective, but PKC increases the peak amplitude of mIPSCs and also favors double exponential decays. Intracellular perfusion of the phosphatase inhibitor microcystin reveals that synaptic GABAA receptors of pyramidal cells, but not those of GCs, are continually phosphorylated by PKA and conversely, dephosphorylated, most likely by phosphatase 1 or 2A. This differential, brain region-specific phosphorylation of GABAA receptors may produce a wide dynamic range of inhibitory synaptic strength in these two regions of the hippocampal formation (Poisbeau, 1999).

Bidirectional changes in the efficacy of neuronal synaptic transmission, such as hippocampal long-term potentiation (LTP) and long-term depression (LTD), are thought to be mechanisms for information storage in the brain. LTP and LTD may be mediated by the modulation of AMPA receptor phosphorylation. LTP and LTD reversibly modify the phosphorylation of the AMPA receptor GluR1 subunit. However, contrary to the hypothesis that LTP and LTD are the functional inverse of each other, LTP and LTD are associated with the phosphorylation and dephosphorylation, respectively, of distinct GluR1 phosphorylation sites. Moreover, the site modulated depends on the stimulation history of the synapse. LTD induction in naive synapses dephosphorylates the major cyclic-AMP-dependent protein kinase (PKA) site, whereas in potentiated synapses the major calcium/calmodulin-dependent protein kinase II (CaMKII) site is dephosphorylated. Conversely, LTP induction in naive synapses and depressed synapses increases phosphorylation of the CaMKII site and the PKA site, respectively. LTP is differentially sensitive to CaMKII and PKA inhibitors depending on the history of the synapse. These results indicate that AMPA receptor phosphorylation is critical for synaptic plasticity, and that identical stimulation conditions recruit different signal-transduction pathways depending on synaptic history (Lee, 2000).

Regulation of N-methyl-D-aspartate (NMDA) receptor activity by kinases and phosphatases contributes to the modulation of synaptic transmission. Targeting of these enzymes near the substrate is proposed to enhance phosphorylation-dependent modulation. Yotiao, an NMDA receptor-associated protein, binds the type I protein phosphatase (PP1) and the adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (PKA) holoenzyme. Anchored PP1 is active, limiting channel activity, whereas PKA activation overcomes constitutive PP1 activity and confers rapid enhancement of NMDA receptor currents. Hence, yotiao is a scaffold protein that physically attaches PP1 and PKA to NMDA receptors to regulate channel activity (Westphal, 1999).

Compartmentalization of glutamate receptors with the signaling enzymes that regulate their activity supports synaptic transmission. Two classes of binding proteins organize these complexes: the MAGUK proteins that cluster glutamate receptors and AKAPs that anchor kinases and phosphatases. Glutamate receptors and PKA are recruited into a macromolecular signaling complex through direct interaction between the MAGUK proteins, PSD-95 and SAP97, and AKAP79/150. The SH3 and GK regions of the MAGUKs mediate binding to the AKAP. Cell-based studies indicate that phosphorylation of AMPA receptors is enhanced by a SAP97-AKAP79 complex that directs PKA to GluR1 via a PDZ domain interaction. Since AMPA receptor phosphorylation is implicated in regulating synaptic plasticity, these data suggest that a MAGUK-AKAP complex may be centrally involved (Colledge, 2000).

Phosphorylation of glutamate receptors is a critical regulatory event in the control of synaptic function and plasticity. Evidence is provided for the existence of a macromolecular transduction unit in which PKA is targeted to glutamate receptors through the direct interaction of two distinct sets of synaptic organizing molecules -- the MAGUK proteins and AKAP79/150. These interactions increase the complexity of signaling networks at excitatory synapses and may provide a structural framework that permits preferential targeting of kinases to glutamate receptors. Presumably, such a highly organized kinase-substrate complex ensures rapid and efficient phosphorylation of ion channels in response to local synaptic signals (Colledge, 2000).

The MAGUK proteins provide the central scaffold upon which the complex is assembled. The N-terminal PDZ domains of PSD-95 and SAP97, two members of the MAGUK protein family, bind to the tails of NMDA and AMPA receptor subunits, respectively. AKAP79/150 and its associated kinases can be recruited to these glutamate receptor complexes via interaction with the C-terminal SH3 and GK domains of the MAGUKs. The demonstration that two independent sites of contact mediate interaction between AKAP79/150 and MAGUK proteins is interesting in light of other mapping studies that have defined linear sequences of 4-6 amino acids as ligands for PDZ, SH2, and SH3 domains. Certainly, multiple sites of contact are not unprecedented and are likely to provide additional stability to a given protein complex. For example, the KA2 subunit of the kainate receptor, like AKAP79, binds to both the SH3 and GK domains of PSD-95. In addition, AKAP79/150 appears to bind to the beta2 adrenergic receptor through sites in both the third intracellular loop and the C-terminal tail. Interestingly, mutations in the SH3 and GK domains of the Drosophila MAGUK Discs large produce severe phenotypes, suggesting that these modules mediate interactions that are critical for regulating MAGUK function. Furthermore, deletion of these regions of PSD-95 in mice produces defects in synaptic plasticity that have been attributed to altered downstream signaling events. A potential explanation for these observations is that the AKAP79/150 signaling scaffold no longer can be recruited to glutamate receptors through interaction with MAGUK proteins (Colledge, 2000 and references therein).

AKAP79/150 previously has been shown to provide a scaffold for three signaling enzymes: PKA, PKC, and calcineurin. Interestingly, PSD-95 competes with calcineurin for binding to AKAP79/150 in vitro. Preliminary mapping experiments suggest that the two proteins do not share the same binding site on the AKAP, since a deletion mutant that does not bind to calcineurin still binds to PSD-95. Thus, a more likely explanation is that PSD-95 binding to AKAP79/150 sterically hinders interaction with calcineurin. These data support the notion that, when bound to MAGUKs, AKAP79/150 may preferentially target kinases but not phosphatases to certain glutamate receptors at the PSD. This could provide a mechanism to favor ion channel phosphorylation through preferential recruitment of regulatory kinases (Colledge, 2000).

While these results clearly argue for a role for anchored PKA in receptor phosphorylation, targeted phosphatases are also certain to participate in receptor dephosphorylation. However, interaction of AKAP79 with MAGUKs appears to exclude the phosphatase calcineurin from the complex. One possibility is that phosphatases may be recruited to AMPA receptors through anchoring proteins other than AKAP79/150. In fact, recent reports suggest that the phosphatase PP1 may be targeted to AMPA receptor complexes through its association with spinophilin. Kinase-phosphatase targeting to some NMDA receptors may be more direct. Through interaction with the NR1-1A splice variant, the anchoring protein yotiao targets both PKA and active PP1 to NMDA receptor complexes, conferring bidirectional regulation of NMDA receptor activity. When considered in light of the present data, this raises the intriguing possibility that signaling enzymes may be recruited to certain NMDA receptors through simultaneous association with two anchoring proteins: yotiao and AKAP79 (Colledge, 2000 and references therein).

Phosphorylation of the cytoplasmic tail of GluR1 potentiates receptor function. CaMKII increases the unitary channel conductance via phosphorylation of Ser-831, while PKA phosphorylation of Ser-845 increases the peak open probability. Phosphorylation-dependent changes in AMPA receptor activity have been proposed to underlie some aspects of LTP and LTD. For example, CamKII phosphorylation appears to be essential for the induction of hippocampal LTP, while recent studies have implicated a role for PKA in LTD. The present results suggest that AKAP79/150 functions as an important player in the postsynaptic regulation of excitatory transmission by targeting PKA to AMPA receptors. Specifically, cAMP-dependent phosphorylation of Ser-845, a known PKA site in GluR1, is enhanced when the kinase is targeted to the channel via a SAP97-AKAP79 complex. This enhancement in phosphorylation is significantly reduced when a PKA anchoring-defective form of AKAP79 is substituted in the complex. Furthermore, a mutation in the PDZ binding site in the tail of GluR1, which uncouples the receptor from SAP97, reduces the basal level of phosphorylation of Ser-845 compared to wild-type GluR1. Together, these results suggest that phosphorylation of Ser-845 is mediated through a SAP97-AKAP79 complex that targets PKA to GluR1 via a PDZ domain interaction. This is particularly interesting in light of recent evidence implicating a GluR1-PDZ domain interaction in the delivery of AMPA receptors into synapses. These data suggest that recruitment of a SAP97-AKAP79-PKA complex may play a role in this process. Manipulation of these protein-protein interactions in animals should provide models to study the role of this synaptic signaling unit in regulating glutamate receptor function in vivo (Colledge, 2000 and references therein).

Modulation of postsynaptic AMPA receptors in the brain by phosphorylation may play a role in the expression of synaptic plasticity at central excitatory synapses. It is known from biochemical studies that GluR1 AMPA receptor subunits can be phosphorylated within their C terminal by cAMP-dependent protein kinase A (PKA), which is colocalized with the phosphatase calcineurin (i.e., phosphatase 2B). The effect of PKA and calcineurin has been studied on the time course, peak open probability, and single-channel properties of glutamate evoked responses for neuronal AMPA receptors and homomeric GluR1(flip) receptors recorded in outside-out patches. Inclusion of purified catalytic subunit Calpha-PKA in the pipette solution increases neuronal AMPA receptor P(O,PEAK) compared with recordings made with calcineurin included in the pipette. Similarly, Calpha-PKA increases peak open probability for recombinant GluR1 receptors compared with patches excised from cells cotransfected with a cDNA encoding the PKA peptide inhibitor PKI or patches with calcineurin included in the pipette. Neither PKA nor calcineurin alters the amplitude of single-channel subconductance levels, weighted mean unitary current, mean channel open period, burst length, or macroscopic response waveform for recombinant GluR1 receptors. Substitution of an amino acid at the PKA phosphorylation site (S845A) on GluR1 eliminates the PKA-induced increase in peak open probability, whereas the mutation of a Ca(2+), calmodulin-dependent kinase II and PKC phosphorylation site (S831A) is without effect. These results suggest that AMPA receptor peak response open probability can be increased by PKA through phosphorylation of GluR1 Ser845 (Banke, 2000).

The capsaicin receptor, VR1 (also known as TRPV1), is a ligand-gated ion channel expressed on nociceptive sensory neurons that responds to noxious thermal and chemical stimuli. Capsaicin responses in sensory neurons exhibit robust potentiation by cAMP-dependent protein kinase (PKA). PKA reduces VR1 desensitization and directly phosphorylates VR1. In vitro phosphorylation, phosphopeptide mapping, and protein sequencing of VR1 cytoplasmic domains delineate several candidate PKA phosphorylation sites. Electrophysiological analysis of phosphorylation site mutants clearly pinpoints Ser116 as the residue responsible for PKA-dependent modulation of VR1. Given the significant roles of VR1 and PKA in inflammatory pain hypersensitivity, VR1 phosphorylation at Ser116 by PKA may represent an important molecular mechanism involved in the regulation of VR1 function after tissue injury (Bhave, 2002).

The regulation of AMPA receptor channels by serotonin signaling in pyramidal neurons of prefrontal cortex (PFC) was studied. Application of serotonin reduced the amplitude of AMPA-evoked currents, an effect mimicked by 5-HT1A receptor agonists (see Drosophila Serotonin receptor 1A) and blocked by 5-HT1A antagonists, indicating the mediation by 5-HT1A receptors. The serotonergic modulation of AMPA receptor currents was blocked by protein kinase A (PKA) activators and occluded by PKA inhibitors. Inhibiting the catalytic activity of protein phosphatase 1 (PP1) also eliminated the effect of serotonin on AMPA currents. Furthermore, the serotonergic modulation of AMPA currents was occluded by application of the Ca(2+)/calmodulin-dependent kinase II (CaMKII) inhibitors and blocked by intracellular injection of calmodulin or recombinant CaMKII. Application of serotonin or 5-HT1A agonists to PFC slices reduced CaMKII activity and the phosphorylation of AMPA receptor subunit GluR1 at the CaMKII site in a PP1-dependent manner. It is concluded that serotonin, by activating 5-HT1A receptors, suppress glutamatergic signaling through the inhibition of CaMKII, which is achieved by the inhibition of PKA and ensuing activation of PP1. This modulation demonstrates the critical role of CaMKII in serotonergic regulation of PFC neuronal activity, which may explain the neuropsychiatric behavioral phenotypes seen in CaMKII knockout mice (Cai, 2002).

Neurotransmitters modulate sodium channel availability through activation of G protein-coupled receptors, cAMP-dependent protein kinase (PKA), and protein kinase C (PKC). Voltage-dependent slow inactivation also controls sodium channel availability, synaptic integration, and neuronal firing. This study shows by analysis of sodium channel mutants that neuromodulation via PKA and PKC enhances intrinsic slow inactivation of sodium channels, making them unavailable for activation. Mutations in the S6 segment in domain III (N1466A,D) either enhance or block slow inactivation, implicating S6 segments in the molecular pathway for slow inactivation. Modulation of N1466A channels by PKC or PKA is increased, whereas modulation of N1466D is nearly completely blocked. These results demonstrate that neuromodulation by PKA and PKC is caused by their enhancement of intrinsic slow inactivation gating. Modulation of slow inactivation by neurotransmitters acting through G protein-coupled receptors, PKA, and PKC is a flexible mechanism of cellular plasticity controlling the firing behavior of central neurons (Chen, 2006).

Table of contents

cAMP-dependent protein kinase 1: Biological Overview | Evolutionary Homologs | Regulation | Protein Interactions | Developmental Biology | Effects of Mutation | References

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