Dopaminergic tone regulates transient potassium current maximal conductance through a translational mechanism requiring D1Rs, cAMP/PKA, Erk and mTOR
© Rodgers et al.; licensee BioMed Central Ltd. 2013
Received: 21 June 2013
Accepted: 7 November 2013
Published: 13 November 2013
Dopamine (DA) can produce divergent effects at different time scales. DA has opposing immediate and long-term effects on the transient potassium current (IA) within neurons of the pyloric network, in the Panulirus interruptus stomatogastric ganglion. The lateral pyloric neuron (LP) expresses type 1 DA receptors (D1Rs). A 10 min application of 5-100 μM DA decreases LP IA by producing a decrease in IA maximal conductance (Gmax) and a depolarizing shift in IA voltage dependence through a cAMP-Protein kinase A (PKA) dependent mechanism. Alternatively, a 1 hr application of DA (≥5 nM) generates a persistent (measured 4 hr after DA washout) increase in IA Gmax in the same neuron, through a mechanistic target of rapamycin (mTOR) dependent translational mechanism. We examined the dose, time and protein dependencies of the persistent DA effect.
We found that disrupting normal modulatory tone decreased LP IA. Addition of 500 pM-5 nM DA to the saline for 1 hr prevented this decrease, and in the case of a 5 nM DA application, the effect was sustained for >4 hrs after DA removal. To determine if increased cAMP mediated the persistent effect of 5nM DA, we applied the cAMP analog, 8-bromo-cAMP alone or with rapamycin for 1 hr, followed by wash and TEVC. 8-bromo-cAMP induced an increase in IA Gmax, which was blocked by rapamycin. Next we tested the roles of PKA and guanine exchange factor protein activated by cAMP (ePACs) in the DA-induced persistent change in IA using the PKA specific antagonist Rp-cAMP and the ePAC specific agonist 8-pCPT-2′-O-Me-cAMP. The PKA antagonist blocked the DA induced increases in LP IA Gmax, whereas the ePAC agonist did not induce an increase in LP IA Gmax. Finally we tested whether extracellular signal regulated kinase (Erk) activity was necessary for the persistent effect by co-application of Erk antagonists PD98059 or U0126 with DA. Erk antagonism blocked the DA induced persistent increase in LP IA.
These data suggest that dopaminergic tone regulates ion channel density in a concentration and time dependent manner. The D1R- PKA axis, along with Erk and mTOR are necessary for the persistent increase in LP IA induced by high affinity D1Rs.
The STNS comprises several motor networks and has long served as an ideal model system for studies of neuromodulation . The pyloric circuit is a 14-neuron network located exclusively within the stomatogastric ganglion (STG, Figure 1A) that is modulated by DA . The STNS dopaminergic system is well defined [7–15]. L-cells within the commissural ganglia (COGs, Figure 1A) secrete DA into the hemolymph . Since the STG resides in a blood vessel and is bathed by hemolymph , this neurohormonal DA serves as a source of tonic DA transmission to pyloric neurons, predicted to be in the pM-nM range [5, 16]. In addition, modulatory DA projection neurons in the COGs use volume transmission whereby DA is released into open synapses and diffuses to its target sites before reuptake . In other systems volume transmission results in tonic nM DA in the extracellular space that can rise to μM levels near the release sites of bursting DA neurons [17–19]. DA receptors are divided into two broad classes, type 1 (D1Rs) and type 2 (D2Rs). The lobster genome contains two D1Rs and one D2R [7, 8]. These receptors signal through canonical pathways in the native system [9, 14] and behave exactly like their mammalian counterparts when expressed in human embryonic kidney cells [7, 8].
In order to better understand the roles of tonic and phasic DA transmissions, we have examined the effects of nM vs. μM DA on identified pyloric neurons. The data suggest tonic and phasic DA have distinct roles because the two concentrations produced opposing persistent vs. immediate effects on IA, respectively . The channels mediating IA are encoded by the shal (Kv4) gene in crustaceans [20–22]. IA is active at sub-threshold voltages, and helps determine the rate of post-inhibitory rebound and spike frequency in pyloric neurons .
There is one lateral pyloric neuron (LP) in the pyloric circuit that expresses D1Rs but not D2Rs . Pyloric neurons show spontaneous, rhythmic oscillations in membrane potential and burst firing (Figure 1B). A 10 min bath application of nM DA has no immediate effect on neuronal output, but bath application of μM DA immediately alters LP activity (Figure 1B), including an increase cycle frequency, a decrease burst duration, and a phase advance mediated, in part, by decreasing LP IA[6, 14, 24]. The threshold for this action is ~ μM  and is therefore likely mediated by low affinity D1Rs. Whereas nM DA has no immediate effect, it can act at high affinity LP D1Rs to persistently alter LP IA: A 1 hr application of 5 nM DA followed by 3 hr wash produced a persistent ~25% increase in LP IA Gmax relative to controls that did not receive DA .
The signaling pathways that transduce DA’s immediate and persistent effects appear to be distinct. Similar to the situation in mammals , lobster D1Rs can couple with Gs and Gq [7, 9]. The immediate decrease in LP IA was mediated by a D1R-AC-cAMP-PKA dependent pathway . The pathway mediating the DA-induced persistent increase in LP IA is unknown, but it is both translation- and mTOR-dependent . Several intracellular signaling pathways can modulate the activity of the serine-threonine kinase, mTOR [26–29]. The goal of this work was to understand the dose and time dependencies and the signaling proteins involved in the DA-induced, persistent increase in LP IA. Here we show that dopaminergic tone regulates IA density through the D1R-PKA axis, Erk and mTOR.
The persistent effect is both time and dose dependent
We next examined if the effect persisted upon DA washout. Experiments were repeated for control, 500 pM and 5 nM preparations. DA or saline (control) was applied for 1 hr and then DA was washed out for 1 hr, 4 hr, or 18 hrs followed by TEVC in blocking saline (see Methods) to measure LP IA (Figure 2A). Data for each experiment were normalized by the mean for control at that time point. Control means varied less than 10% between 1 hr and 18 hr. After a 1 hr DA washout (i.e. 2 hr time point), the effect of 500 pM DA on LP IA Gmax was no longer significant, whereas the significant increase produced by 5 nM DA was sustained (ANOVA F2,15 = 6.51, p = 0.0101, Dunnet’s post hoc, 5 nM vs ctrl, p < 0.01) (Figure 2B). After a 4 hr DA washout (i.e., 5 hr time point) average LP IA Gmax decreased to control levels in the 500 pM treated preparations but remained significantly elevated in the 5 nM treated preparations compared to control (ANOVA F2,20 = 5.411, p = 0.013, Dunnet’s post hoc 5 nM vs ctrl, p < 0.01, Figure 2B). IA Gmax remains elevated out to 18 hrs after DA administration  (Figure 2B).
The previous experiments revealed that the persistent effect of nM DA was observable, compared to controls, by 1 hr after the start of DA administration. To examine the time course for the development of the DA mediated increase in IA we measured IA repeatedly during a 1 hr 5 nM DA or saline (control) application (Figure 2C). To more carefully examine changes over time, we normalized all the values to t = 0 (Figure 2D) (There were no differences at t = 0 between control and DA treated preparations (t-test, p = 0.19)). We then performed mixed-model repeated measures ANOVA with time as the within-subjects factor and treatment (5 nM DA vs. Control) as the between-subjects factor. There was a significant effect of treatment (F1,9 = 7.10, p = 0.026), but not of time (F2,9 = 3.05, p = 0.0975). Post hoc comparisons, with Dunn-Sidak adjustments, revealed significant differences between treatments at 60 min (p = 0.0247) (Figure 2D). By 60 min, average IA Gmax increased by ~10%, in DA-treated preparations and decreased by ~13% in control preparations.
The persistent effect is mediated by increased cAMP
cAMP acts through PKA to increase IA Gmax
There are several known downstream effectors of cAMP , notably PKA , ePACs [32, 33], and cyclic-nucleotide gated channels . We first tested whether cAMP mediated its effects on LP IA through ePAC by employing the ePAC specific agonist, 8-pCPT-2′-O-Me-cAMP. This cAMP analogue has been used successfully to differentially activate ePAC1/2 as opposed to PKA  in a host of phylogenetically divergent animals, including crustaceans . We applied 50 μM 8-cpt-cAMP or saline (control) for 1 hr, followed by a 1 hr wash and TEVC to measure LP IA. 8-cpt-cAMP had no effect on LP IA Gmax relative to control (t-test, p = 0.72), suggesting that the persistent effect of DA on LP IA was not mediated through ePAC activation. At present there are no effective antagonists for ePACs.
Erk activation is required for the DA mediated increase in IA Gmax
U0126 affects the time constant of inactivation
Tonic DA regulates IAin a time and dose dependent manner
We showed that dopaminergic tone influences IA density. In the absence of tonic DA, average IA Gmax decreased by 13% over the course of 1 hr. Average IA Gmax did not decrease during a 1 hr application of ≥500 pM DA, but dropped to control levels when DA was removed. Average IA Gmax increased by ~10% during a 1 hr application of 5 nM DA and the increase was sustained for at least 5 hrs after removal of DA. 5 μM DA produced the same persistent increase in LP IA Gmax. We interpret the data to mean that dopaminergic tone acts at high affinity D1Rs to persistently augment LP IA density. Our findings are consistent with previous work that suggests that tonic application of modulators can regulate surface expression of ion channels [43–45].
One interpretation of these data is that dopaminergic tone increases the ratio of the rate of shal channel insertion into versus removal from the plasma membrane. Upon removal of DA, the ratio will decrease, and IA will decline according to the half-life of the channel. Since the DA-induced increase is translation-dependent, it is tempting to speculate that DA increases the pool of shal channels available for insertion. Alternatively, or in addition, it is also possible that DA might alter the subunit composition of the shal channels by incorporating different shal isoforms into the tetrameric channel  or by altering auxiliary subunits that interact with the alpha subunits , which are known to influence conductance . It is also possible that DA alters levels of proteins involved in trafficking or endocytosis of shal channels. Since TEVC was always performed in the presence of TTX to block activity, we cannot rule out the possibility that decreases in activity may also contribute to changes in IA Gmax. Indeed, both neuronal activity acting through changes in Ca2+ and neuromodulators can alter cAMP levels in arthropods via the adenylyl cyclase, rutabaga [48, 49].
Immediate and persistent regulation of IAboth utilize cAMP-PKA axis
The immediate and persistent effects of DA that decrease and increase IA, respectively, are both mediated by a DA activated increase in cAMP and PKA activity . It is unclear where the pathways diverge. LP cells express two different D1Rs: D1αPan and D1RβPan [7, 14]. These distinct receptors could mediate the observed high and low affinity effects. This need not be the case. Receptors exist in multiprotein signaling complexes called signalplexes [50–52] and the same receptor could be incorporated into distinct signalplexes that generate unique cAMP signals. It has been demonstrated that agonists acting at receptors that positively couple with cAMP can simultaneously generate large, temporally complex, local signals and sustained global signals [53–56]. Compartmentilization of cAMP signaling has been demonstrated to be critical in mediating differential downstream effects of cAMP and preventing non-specific activity of cAMP effectors . cAMP signals can be constrained by differential PKA compartmentalization via A Kinase anchoring proteins (AKAPs)  and/or by differential phosphodiesterase localization . D1Rs are predominately localized to terminals in fine neurites . Previous cAMP imaging studies on STG neurons showed that continuous application of modulators, including DA, initially produced a cAMP signal in the terminals that eventually spread throughout the cell . Since the persistent effect is induced by continuous exposure to DA, that could result in more global changes in shal channels than the immediate effect.
PKA and ERK contribute to the persistent increase in LP IA Gmax
Erk activation is required for the persistent increase in IA Gmax. Both MEK antagonists blocked the persistent effect when co-applied with 5 nM DA. It is not clear if ERK and PKA are acting in parallel or series. The intracellular signaling pathway mediating the persistent increase in LP IA shows a remarkable overlap with many proteins involved in L-3, 4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia (LID) [58–60]. Specifically, both pathways involve a D1R mediated increase in cAMP, PKA activation, increase in Erk activity, and finally mTORC1 activation. LID is attenuated by PKA  and mTOR antagonism . Independent dual activation of cAMP/PKA axis and Erk by D1Rs has been observed in LID, where L-DOPA treated Gαolf deficient mice showed decreased PKA phosphorylation, but no change in Erk activation . The Erk pathway has multiple points of interaction with proteins affecting mTOR activity , and based on this data, it is impossible to say which protein pathways mediate this effect. Interestingly, the neurotrophic factor Neuritin, which also increases IA (Kv4.2) in a dose and time dependent manner in mammalian neurons, requires both Erk and mTOR , suggesting many components of modulatory tone may act together to determine IA density.
DA acts at high affinity receptors to increase IA Gmax through a translation dependent mechanism that requires a functional D1R-PKA axis, Erk and mTOR.
California spiny lobsters, Panulirus interruptus, were purchased from Catalina Offshore Products (San Diego, CA) and Marinus Scientific (Long Beach, CA) and housed in saltwater aquaria at Georgia State University (Atlanta, GA). Animals were a mix of both male and females.
This research was carried out in accordance with the IACUC standards for use of animals in research at Georgia State University.
All drugs were administered to the STG via superfusion. DA was administered for 1 hour in all cases. To minimize oxidation, DA was made fresh and exchanged after 30 min. Dosages of PKA antagonist Rp-cAMP (1 mM) (Sigma), and mTOR antagonist rapamycin (100 nM) (Sigma) were chosen based previously established effective doses in the STG [4, 14]. The ePAC agonist (Tocris) was applied at 50 μM . ErK activity was blocked by the use of MEK antagonists PD98059 (50 μM, Invivogen) and U0126 (50 μM, Tocris) based on previously shown effective dosages in the white shrimp, F. indicus, and dissolved in DMSO. Drugs were applied to the preparation 10 min before the application of DA.
STNS Dissection, Pyloric cell identification
Lobsters were anaesthetized on ice for at least 30 min, followed by the dissection of the STNS, as previously described . The STNS was pinned in a Sylgard-lined dish. The STG was desheathed and petroleum jelly well was constructed around it. Using a Dynamax peristaltic pump (Rainin), the STG was superfused with Panulirus (P.) saline (in mM: 479 NaCl, 12.8 KCl, 13.7 CaCl2, 39 Na2SO4, 10 MgSO4, 2 Glucose, 4.99 HEPES, 5 TES; pH 7.4).
Experiments were performed at room temperature. Temperature was continuously monitored with a miniature probe in the bath. The temperature changed by less than 1°C throughout the course of the day (the change ranged from 0.1 to 0.9°C on any given day), and by only 3°C across all experiments (19-22°C).
Cells were identified using previously described standard intracellular and extracellular recording techniques. Intracellular somatic recordings (such as those seen in Figure 1B) were obtained using 20–40 MΩ glass microelectrodes filled with 3 M KCl and Axoclamp 2B or 900A amplifiers (Molecular Devices, Foster City, CA). Extracellular recordings of identified motor neurons were obtained using a differential AC amplifier (A-M Systems, Everett, WA) with stainless steel pin electrodes. LP neurons were identified by their distinct waveforms, the timing of their voltage oscillations, and correlation of spikes on the extracellular and intracellular recordings (Figure 1B).
Two-electrode voltage clamp
A portion of the stomatogastric nerve was isolated in a petroleum jelly well containing isotonic sucrose; descending inputs were removed by cutting the STN in the sucrose bath 1 hour prior to TEVC. The STG was superfused continuously with blocking saline, which consisted of P. saline containing picrotoxin (10-6 M) to block glutamatergic synaptic inputs and voltage-dependent ion channel blockers: tetrodotoxin (TTX, 100 nM, INa), tetraethylammonium (TEA, 20 mM, IK(V) and IK(Ca)), and cadmium chloride (CdCl2, 200 μM, ICa). LP cells were impaled with two low resistance microelectrodes (8–10 MΩ) filled with 3 M KCl. The holding potential was -50 mV. IA activation was measured by two different protocols, A and B. Protocol A: IA was elicited by a series of depolarizing steps (500 ms) ranging from -50 to +60 mV in 10 mV increments that were or were not preceded by a 200 ms prepulse to -90 mV to remove resting inactivation of A type K + channels. IA was obtained by digitally subtracting the current obtained without a prepulse from currents obtained with a prepulse. After digital subtraction, the peak current was converted to conductance (G = Ipeak/(Vm-Ek), plotted against voltage and fit using a 1st order Boltzmann equation to determine the voltage of half activation and maximal conductance. Protocol B: here the voltage protocol was modified to minimize the effects of repeated depolarization. This protocol was only used in the experiments shown in Figure 2D. IA activation was measured with 8 depolarizing steps that ranged from -50 mV to +20 mV, and the minimum tail current was subtracted from peak current for each sweep. Data was again fit with a 1st order Boltzmann equation to determine the voltage of half activation and maximal conductance. Steady state inactivation was measured by a series of sweeps that varied the range of the 200 ms prepulse from -110 to -20 mv in 10 mV increments followed by a constant step to 20 mV (500 ms). To further isolate IA, a depolarizing prepulse to -20 mV, followed by a test pulse to 20 mV was digitally subtracted from each inactivation trace. Peak current was plotted for each voltage and fit with a 1st order boltzmann equation to derive voltage of half inactivation.
The data were checked for normality and analyzed using parametric statistics. Data were analyzed using Prism Statistical software package (Graphpad) and SAS version 8.1 (SAS Institute Inc.). Significance threshold was set at p < 0.05 in all cases. Statistical outliers were excluded based on Chauvenet’s Criterion. Means are presented ± Standard Deviation.
The authors would like to thank Tim Dever for his technical help and for care of the animals. The authors would also like to thank Dr. Ryan Earley for his help with statistical analyses. The authors would also like to thank the NIH for their funding support of this research through DA024039 to Dr. Baro and R01 DK071801 to Dr. Li.
- Schultz W: Getting formal with dopamine and reward. Neuron. 2002, 36 (2): 241-263. 10.1016/S0896-6273(02)00967-4.View ArticlePubMed
- Schultz W: Multiple dopamine functions at different time courses. Annu Rev Neurosci. 2007, 30: 259-288. 10.1146/annurev.neuro.28.061604.135722.View ArticlePubMed
- Grace AA: Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience. 1991, 41 (1): 1-24. 10.1016/0306-4522(91)90196-U.View ArticlePubMed
- Rodgers EW, Krenz WD, Baro DJ: Tonic dopamine induces persistent changes in the transient potassium current through translational regulation. J Neurosci. 2011, 31 (37): 13046-13056. 10.1523/JNEUROSCI.2194-11.2011.PubMed CentralView ArticlePubMed
- Marder E, Bucher D: Understanding circuit dynamics using the stomatogastric nervous system of lobsters and crabs. Ann Rev Physiol. 2007, 69: 291-316. 10.1146/annurev.physiol.69.031905.161516.View Article
- Harris-Warrick RM, Johnson BR, Peck JH, Kloppenburg P, Ayali A, Skarbinski J: Distributed effects of dopamine modulation in the crustacean pyloric network. Ann NY Acad Sci. 1998, 860: 155-167. 10.1111/j.1749-6632.1998.tb09046.x.View ArticlePubMed
- Clark MC, Baro DJ: Molecular cloning and characterization of crustacean type-one dopamine receptors: D1alphaPan and D1betaPan. Comp Biochem Physiol B Biochem Mol Biol. 2006, 143 (3): 294-301. 10.1016/j.cbpb.2005.11.017.PubMed CentralView ArticlePubMed
- Clark MC, Baro DJ: Arthropod D2 receptors positively couple with cAMP through the Gi/o protein family. Comp Biochem Physiol B Biochem Mol Biol. 2007, 146 (1): 9-19. 10.1016/j.cbpb.2006.08.018.PubMed CentralView ArticlePubMed
- Clark MC, Khan R, Baro DJ: Crustacean dopamine receptors: localization and G protein coupling in the stomatogastric ganglion. J Neurochem. 2008, 104 (4): 1006-1019. 10.1111/j.1471-4159.2007.05029.x.PubMed CentralView ArticlePubMed
- Oginsky MF, Rodgers EW, Clark MC, Simmons R, Krenz WD, Baro DJ: D(2) receptors receive paracrine neurotransmission and are consistently targeted to a subset of synaptic structures in an identified neuron of the crustacean stomatogastric nervous system. J Comp Neurol. 2010, 518 (3): 255-276. 10.1002/cne.22225.PubMed CentralView ArticlePubMed
- Pulver SR, Marder E: Neuromodulatory complement of the pericardial organs in the embryonic lobster, Homarus americanus. J Comp Neurol. 2002, 451 (1): 79-90. 10.1002/cne.10331.View ArticlePubMed
- Pulver SR, Thirumalai V, Richards KS, Marder E: Dopamine and histamine in the developing stomatogastric system of the lobster Homarus americanus. J Comp Neurol. 2003, 462 (4): 400-414. 10.1002/cne.10767.View ArticlePubMed
- Tierney AJ, Kim T, Abrams R: Dopamine in crayfish and other crustaceans: distribution in the central nervous system and physiological functions. Microsc Res Tech. 2003, 60 (3): 325-335. 10.1002/jemt.10271.View ArticlePubMed
- Zhang H, Rodgers EW, Krenz WD, Clark MC, Baro DJ: Cell specific dopamine modulation of the transient potassium current in the pyloric network by the canonical d1 receptor signal transduction cascade. J Neurophysiol. 2010, 104 (2): 873-884. 10.1152/jn.00195.2010.PubMed CentralView ArticlePubMed
- Sullivan RE, Friend BJ, Barker DL: Structure and function of spiny lobster ligamental nerve plexuses: evidence for synthesis, storage, and secretion of biogenic amines. J Neurobiol. 1977, 8 (6): 581-605. 10.1002/neu.480080607.View ArticlePubMed
- Bucher D, Thirumalai V, Marder E: Axonal dopamine receptors activate peripheral spike initiation in a stomatogastric motor neuron. J Neurosci. 2003, 23 (17): 6866-6875.PubMed
- Frank ST, Krumm B, Spanagel R: Cocaine-induced dopamine overflow within the nucleus accumbens measured by in vivo microdialysis: a meta-analysis. Synapse. 2008, 62 (4): 243-252. 10.1002/syn.20489.View ArticlePubMed
- Owesson-White CA, Roitman MF, Sombers LA, Belle AM, Keithley RB, Peele JL, Carelli RM, Wightman RM: Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens. J Neurochem. 2012, 121 (2): 252-262. 10.1111/j.1471-4159.2012.07677.x.PubMed CentralView ArticlePubMed
- Park J, Takmakov P, Wightman RM: In vivo comparison of norepinephrine and dopamine release in rat brain by simultaneous measurements with fast-scan cyclic voltammetry. J Neurochem. 2011, 119 (5): 932-944. 10.1111/j.1471-4159.2011.07494.x.PubMed CentralView ArticlePubMed
- Baro DJ, Cole CL, Harris-Warrick RM: RT-PCR analysis of shaker, shab, shaw, and shal gene expression in single neurons and glial cells. Receptors Channels. 1996, 4 (3): 149-159.PubMed
- Baro DJ, Levini RM, Kim MT, Willms AR, Lanning CC, Rodriguez HE, Harris-Warrick RM: Quantitative single-cell-reverse transcription-PCR demonstrates that A-current magnitude varies as a linear function of shal gene expression in identified stomatogastric neurons. J Neurosci. 1997, 17 (17): 6597-6610.PubMed
- Baro DJ, Quinones L, Lanning CC, Harris-Warrick RM, Ruiz M: Alternate splicing of the shal gene and the origin of I(A) diversity among neurons in a dynamic motor network. Neuroscience. 2001, 106 (2): 419-432. 10.1016/S0306-4522(01)00261-5.View ArticlePubMed
- Tierney AJ, Harris-Warrick RM: Physiological role of the transient potassium current in the pyloric circuit of the lobster stomatogastric ganglion. J Neurophysiol. 1992, 67 (3): 599-609.PubMed
- Rodgers EW, Fu JJ, Krenz WD, Baro DJ: Tonic nanomolar dopamine enables an activity-dependent phase recovery mechanism that persistently alters the maximal conductance of the hyperpolarization-activated current in a rhythmically active neuron. J Neurosci. 2011, 31 (45): 16387-16397. 10.1523/JNEUROSCI.3770-11.2011.PubMed CentralView ArticlePubMed
- Beaulieu JM, Gainetdinov RR: The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011, 63 (1): 182-217. 10.1124/pr.110.002642.View ArticlePubMed
- Hoeffer CA, Klann E: mTOR signaling: at the crossroads of plasticity, memory and disease. Trends Neurosci. 2010, 33 (2): 67-75. 10.1016/j.tins.2009.11.003.PubMed CentralView ArticlePubMed
- Laplante M, Sabatini DM: mTOR signaling at a glance. J Cell Sci. 2009, 122 (Pt 20): 3589-3594.PubMed CentralView ArticlePubMed
- Mendoza MC, Er EE, Blenis J: The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation. Trends biochem. 2011, 36 (6): 320-328. 10.1016/j.tibs.2011.03.006.View Article
- Proud CG: Cell signaling. mTOR, unleashed. Science. 2007, 318 (5852): 926-927. 10.1126/science.1150653.View ArticlePubMed
- Edwards HV, Christian F, Baillie GS: cAMP: novel concepts in compartmentalised signalling. Semin Cell Dev Biol. 2012, 23 (2): 181-190. 10.1016/j.semcdb.2011.09.005.View ArticlePubMed
- Pidoux G, Tasken K: Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins. J Mol Endocrinol. 2010, 44 (5): 271-284. 10.1677/JME-10-0010.View ArticlePubMed
- Bos JL: Epac proteins: multi-purpose cAMP targets. Trends biochem. 2006, 31 (12): 680-686. 10.1016/j.tibs.2006.10.002.View Article
- Breckler M, Berthouze M, Laurent AC, Crozatier B, Morel E, Lezoualc’h F: Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications. Cell Signal. 2011, 23 (8): 1257-1266. 10.1016/j.cellsig.2011.03.007.View ArticlePubMed
- Biel M: Cyclic nucleotide-regulated cation channels. J Biol Chem. 2009, 284 (14): 9017-9021. 10.1074/jbc.R800075200.PubMed CentralView ArticlePubMed
- Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, Genieser HG, Doskeland SO, Blank JL, Bos JL: A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nature Cell Biol. 2002, 4 (11): 901-906. 10.1038/ncb874.View ArticlePubMed
- Zhong N, Zucker RS: cAMP acts on exchange protein activated by cAMP/cAMP-regulated guanine nucleotide exchange protein to regulate transmitter release at the crayfish neuromuscular junction. J Neurosci. 2005, 25 (1): 208-214. 10.1523/JNEUROSCI.3703-04.2005.View ArticlePubMed
- Carriere A, Cargnello M, Julien LA, Gao H, Bonneil E, Thibault P, Roux PP: Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation. Curr Biol. 2008, 18 (17): 1269-1277. 10.1016/j.cub.2008.07.078.View ArticlePubMed
- Gobert D, Topolnik L, Azzi M, Huang L, Badeaux F, Desgroseillers L, Sossin WS, Lacaille JC: Forskolin induction of late-LTP and up-regulation of 5′ TOP mRNAs translation via mTOR, ERK, and PI3K in hippocampal pyramidal cells. J Neurochem. 2008, 106 (3): 1160-1174. 10.1111/j.1471-4159.2008.05470.x.View ArticlePubMed
- Busca R, Abbe P, Mantoux F, Aberdam E, Peyssonnaux C, Eychene A, Ortonne JP, Ballotti R: Ras mediates the cAMP-dependent activation of extracellular signal-regulated kinases (ERKs) in melanocytes. EMBO J. 2000, 19 (12): 2900-2910. 10.1093/emboj/19.12.2900.PubMed CentralView ArticlePubMed
- Wang L, Liu F, Adamo ML: Cyclic AMP inhibits extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways by inhibiting Rap1. J Biol Chem. 2001, 276 (40): 37242-37249. 10.1074/jbc.M105089200.View ArticlePubMed
- Wei A, Covarrubias M, Butler A, Baker K, Pak M, Salkoff L: K + current diversity is produced by an extended gene family conserved in Drosophila and mouse. Science. 1990, 248 (4955): 599-603. 10.1126/science.2333511.View ArticlePubMed
- Yuan LL, Chen X, Kunjilwar K, Pfaffinger P, Johnston D: Acceleration of K + channel inactivation by MEK inhibitor U0126. Am J Physiol Cell Physiol. 2006, 290 (1): C165-C171.View ArticlePubMed
- Khorkova O, Golowasch J: Neuromodulators, not activity, control coordinated expression of ionic currents. J Neurosci. 2007, 27 (32): 8709-8718. 10.1523/JNEUROSCI.1274-07.2007.PubMed CentralView ArticlePubMed
- Temporal S, Desai M, Khorkova O, Varghese G, Dai A, Schulz DJ, Golowasch J: Neuromodulation independently determines correlated channel expression and conductance levels in motor neurons of the stomatogastric ganglion. J Neurophysiol. 2012, 107 (2): 718-727. 10.1152/jn.00622.2011.PubMed CentralView ArticlePubMed
- Sun X, Milovanovic M, Zhao Y, Wolf ME: Acute and chronic dopamine receptor stimulation modulates AMPA receptor trafficking in nucleus accumbens neurons cocultured with prefrontal cortex neurons. J Neurosci. 2008, 28 (16): 4216-4230. 10.1523/JNEUROSCI.0258-08.2008.PubMed CentralView ArticlePubMed
- Shibata R, Misonou H, Campomanes CR, Anderson AE, Schrader LA, Doliveira LC, Carroll KI, Sweatt JD, Rhodes KJ, Trimmer JS: A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels. J Biol Chem. 2003, 278 (38): 36445-36454. 10.1074/jbc.M306142200.View ArticlePubMed
- An WF, Bowlby MR, Betty M, Cao J, Ling HP, Mendoza G, Hinson JW, Mattsson KI, Strassle BW, Trimmer JS, et al: Modulation of A-type potassium channels by a family of calcium sensors. Nature. 2000, 403 (6769): 553-556. 10.1038/35000592.View ArticlePubMed
- Tomchik SM, Davis RL: Dynamics of learning-related cAMP signaling and stimulus integration in the Drosophila olfactory pathway. Neuron. 2009, 64 (4): 510-521. 10.1016/j.neuron.2009.09.029.PubMed CentralView ArticlePubMed
- Gervasi N, Tchenio P, Preat T: PKA dynamics in a Drosophila learning center: coincidence detection by rutabaga adenylyl cyclase and spatial regulation by dunce phosphodiesterase. Neuron. 2010, 65 (4): 516-529. 10.1016/j.neuron.2010.01.014.View ArticlePubMed
- Bockaert J, Marin P, Dumuis A, Fagni L: The ’magic tail’ of G protein-coupled receptors: an anchorage for functional protein networks. FEBS letters. 2003, 546 (1): 65-72. 10.1016/S0014-5793(03)00453-8.View ArticlePubMed
- Kabbani N, Levenson R: A proteomic approach to receptor signaling: molecular mechanisms and therapeutic implications derived from discovery of the dopamine D2 receptor signalplex. Eur J Pharmacol. 2007, 572 (2–3): 83-93.View ArticlePubMed
- Rex EB, Rankin ML, Yang Y, Lu Q, Gerfen CR, Jose PA, Sibley DR: Identification of RanBP 9/10 as interacting partners for protein kinase C (PKC) gamma/delta and the D1 dopamine receptor: regulation of PKC-mediated receptor phosphorylation. Mol Pharmacol. 2010, 78 (1): 69-80. 10.1124/mol.110.063727.PubMed CentralView ArticlePubMed
- Dyachok O, Isakov Y, Sagetorp J, Tengholm A: Oscillations of cyclic AMP in hormone-stimulated insulin-secreting beta-cells. Nature. 2006, 439 (7074): 349-352. 10.1038/nature04410.View ArticlePubMed
- Nikolaev VO, Bunemann M, Schmitteckert E, Lohse MJ, Engelhardt S: Cyclic AMP imaging in adult cardiac myocytes reveals far-reaching beta1-adrenergic but locally confined beta2-adrenergic receptor-mediated signaling. Circ Res. 2006, 99 (10): 1084-1091. 10.1161/01.RES.0000250046.69918.d5.View ArticlePubMed
- Rich TC, Fagan KA, Tse TE, Schaack J, Cooper DM, Karpen JW: A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell. Proc Natl Acad Sci USA. 2001, 98 (23): 13049-13054. 10.1073/pnas.221381398.PubMed CentralView ArticlePubMed
- Rochais F, Abi-Gerges A, Horner K, Lefebvre F, Cooper DM, Conti M, Fischmeister R, Vandecasteele G: A specific pattern of phosphodiesterases controls the cAMP signals generated by different Gs-coupled receptors in adult rat ventricular myocytes. Circ Res. 2006, 98 (8): 1081-1088. 10.1161/01.RES.0000218493.09370.8e.PubMed CentralView ArticlePubMed
- Hempel CM, Vincent P, Adams SR, Tsien RY, Selverston AI: Spatio-temporal dynamics of cyclic AMP signals in an intact neural circuit. Nature. 1996, 384 (6605): 166-169. 10.1038/384166a0.View ArticlePubMed
- Feyder M, Bonito-Oliva A, Fisone G: L-DOPA-Induced Dyskinesia and Abnormal Signaling in Striatal Medium Spiny Neurons: focus on Dopamine D1 Receptor-Mediated Transmission. Front Behav Neurosci. 2011, 5: 71.PubMed CentralView ArticlePubMed
- Santini E, Feyder M, Gangarossa G, Bateup HS, Greengard P, Fisone G: Dopamine- and cAMP-regulated phosphoprotein of 32-kDa (DARPP-32)-dependent activation of extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) signaling in experimental parkinsonism. J Biol Chem. 2012, 287 (33): 27806-27812. 10.1074/jbc.M112.388413.PubMed CentralView ArticlePubMed
- Santini E, Sgambato-Faure V, Li Q, Savasta M, Dovero S, Fisone G, Bezard E: Distinct changes in cAMP and extracellular signal-regulated protein kinase signalling in L-DOPA-induced dyskinesia. PLoS One. 2010, 5 (8): e12322-10.1371/journal.pone.0012322.PubMed CentralView ArticlePubMed
- Lebel M, Chagniel L, Bureau G, Cyr M: Striatal inhibition of PKA prevents levodopa-induced behavioural and molecular changes in the hemiparkinsonian rat. Neurobiol Dis. 2010, 38 (1): 59-67. 10.1016/j.nbd.2009.12.027.View ArticlePubMed
- Santini E, Heiman M, Greengard P, Valjent E, Fisone G: Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia. Sci Signal. 2009, 2 (80): ra36-10.1126/scisignal.2000308.View ArticlePubMed
- Alcacer C, Santini E, Valjent E, Gaven F, Girault JA, Herve D: Galpha(olf) mutation allows parsing the role of cAMP-dependent and extracellular signal-regulated kinase-dependent signaling in L-3,4-dihydroxyphenylalanine-induced dyskinesia. J Neurosci. 2012, 32 (17): 5900-5910. 10.1523/JNEUROSCI.0837-12.2012.View ArticlePubMed
- Yao JJ, Gao XF, Chow CW, Zhan XQ, Hu CL, Mei YA: Neuritin activates insulin receptor pathway to up-regulate Kv4.2-mediated transient outward K + current in rat cerebellar granule neurons. J Biol Chem. 2012, 287 (49): 41534-41545. 10.1074/jbc.M112.390260.PubMed CentralView ArticlePubMed
- Devaraj H, Natarajan A: Molecular mechanisms regulating molting in a crustacean. Febs J. 2006, 273 (4): 839-846. 10.1111/j.1742-4658.2006.05117.x.View ArticlePubMed
- Selverston AI, Russell DF, Miller JP: The stomatogastric nervous system: structure and function of a small neural network. Prog Neurobiol. 1976, 7 (3): 215-290.View ArticlePubMed
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