Regulation of Kainate Receptors by cAMP-Dependent Protein Kinase and Phosphatases

Abstract

In the mammalian central nervous system, receptors for excitatory amino acid neurotransmitters such as the alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA)-kainate receptor mediate a large fraction of excitatory transmission. Currents induced by activation of the AMPA-kainate receptor were potentiated by agents that specifically stimulate adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A (PKA) activity or were supported by intracellular application of the catalytic subunit of PKA by itself or in combination with cAMP. Furthermore, depression of these currents by a competitive inhibitor of PKA indicates that AMPA-kainate receptors are regulated by endogenous PKA. Endogenous protein phosphatases also regulate these receptors because an inhibitor of cellular phosphates enhanced kainate currents. Modulation of PKA and phosphatases may regulate the function of these receptors and thus contribute to synaptic plasticity in hippocampal neurons.

Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation in Hippocampal Neurons

“…Initially, we tried perforated patch recording using nystatin, but we did not have significant success with this technique, because electrode occlusion by nystatin often occurred well before the planned end points of our recording sessions. Wang et al (1991) have shown that ATP-regenerating pipette solutions are critical for maintaining robust whole-cell kainate-AMPA currents in hippocampal neurons. Our electrode solution contained, in addition to ATP and GTP, phosphocreatine and creatine phosphokinase, agents that were probably critical for recording over periods of 90 -150 min.…”

“…The list of potential candidates is long, but PKA-mediated phosphorylation of glutamatergic receptor subunit 1 (GluR1) at serine-845 is important for the bidirectional regulation of hippocampal synaptic plasticity (Banke et al, 2000;Lee et al, 2000) [for GluR4 data, see Carvalho et al (1999)], and PKA activators can increase EPSC amplitudes by promoting PKA-mediated phosphorylation of AMPA receptors (Wang et al, 1991). NMDA receptor-mediated currents are also increased by PKA-mediated phosphorylation (Raman et al, 1996;Leonard and Hell, 1997).…”

“…Coapplication of the adenylyl cyclase activator FSK and the cyclic nucleotide phosphodiesterase inhibitor IBMX can occlude longlasting LTP evoked by subsequent tetanic stimulation (Frey et al, 1993;Huang and Kandel, 1994), suggesting that PKA activation is both necessary and sufficient to induce long-lasting LTP. However, the extracellular application of FSK and IBMX could activate PKA both presynaptically and postsynaptically, and FSK has been shown to enhance non-NMDA receptor-mediated currents in cultured hippocampal neurons (Greengard et al, 1991;Wang et al, 1991). To determine the locus of the FSK response, we compared the response of evoked EPSCs to FSK and IBMX coapplication in the presence or absence of intracellular postsynaptic PKI 6 -22 .…”

17β-Estradiol Potentiates Kainate-Induced Currents via Activation of the cAMP Cascade

“…Several studies have suggested that brain second messenger systems, well known for altering nerve cell activity by modifying characteristics of voltage-gated channels (Kaczmarek and Levitan, 1987), also play a role in the modulation of ligand-gated ionotropic glutamate receptors (Wang et al, 1991(Wang et al, , 1994Blackstone et al, 1994;Lieberman and Mody, 1994). In cultured hippocampal neurons, the whole-cell current response to glutamate and kainate was enhanced by forskolin, an activator of adenylate cyclase, and the opening frequency and the mean open time of the non-NMDA-type glutamate receptor channel was increased by adenosine 3',5'-monophosphate-dependent protein kinase (PKA) (Greengard et al, 1991).…”

Regulation of Phosphorylation of the GluR1 AMPA Receptor in the Neostriatum by Dopamine and PsychostimulantsIn Vivo

“…For example, activation of cAMP-dependent protein kinase (PKA) in hippocampal (Greengard et al, 1991;Wang et al, 1991;Rosenmund et al, 1994;Kameyama et al, 1998) or neostriatal neurons increases AMPA currents recorded from these cells. The notion that these effects occur as the result of phosphorylation of the receptor is supported by the observation that the GluR1 subunit is phosphorylated in response to PKA activation in human embryonic kidney-293 cells (Blackstone et al, 1994;Tan et al, 1994) (but see McGlade-McCulloh et al, 1993).…”