Gravin Orchestrates Protein Kinase A and β2-Adrenergic Receptor Signaling Critical for Synaptic Plasticity and Memory

Abstract

A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of Protein Kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Further, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK, are attenuated in the CA1 region of the hippocampus in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage.

Persistent Electrical Activity in Primary Nociceptors after Spinal Cord Injury Is Maintained by Scaffolded Adenylyl Cyclase and Protein Kinase A and Is Associated with Altered Adenylyl Cyclase Regulation

“…Increases in cAMP synthesis in primary afferent neurons have long been known to participate in various responses to bodily injury, including axonal regeneration (Siddiq and Hannila, 2015) and sensitization (Gold and Gebhart, 2010). In nociceptors, increased cAMP synthesis contributes to sensitization by inflammatory signals lasting several hours (e.g., Taiwo et al, 1989;Cui and Nicol, 1995;Hingtgen et al, 1995;Kress et al, 1996;Gold et al, 1998), and the acute sensitization of nociceptors by heat or prostaglandin E 2 depends upon AKAP150-PKA complexes (Jeske et al, 2008;Schnizler et al, 2008;Efendiev et al, 2013;Fischer and McNaughton, 2014). Surprisingly few studies have investigated whether AC-PKA signaling also contributes to the maintenance of persistent hyperexcitability of nociceptors.…”

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

“…Moreover, GluA1 serine 845 phosphorylation induced by b-AR activation in hippocampal neurons is disrupted in mice with a null mutation in the AKAP5 gene, which encodes AKAP79/150 . The induction of LTP by TPS in the presence of ISO is also abolished in AKAP5 mutants ) and in hippocampal slices from wild-type mice that are exposed to membrane-permeant peptide inhibitors that disrupt PKA binding to AKAPs (Havekes et al 2012). Thus, b-AR signaling complexes are crucial for both AMPAR phosphorylation and facilitation of LTP induction.…”

“…For example, b-AR activation enables the induction of protein synthesis-dependent L-LTP by a single 100-Hz train of HFS (Gelinas and Nguyen 2005;Ma et al 2011). Moreover, u-pulse stimulation (TPS; 150-900 stimulation pulses delivered at 5 -10 Hz), a pattern of synaptic stimulation that alone has little or no lasting effect on synaptic strength, can induce LTP if delivered in the presence of b-AR agonists (Thomas et al 1996;Katsuki et al 1997;Moody et al 1998;Winder et al 1999;Brown et al 2000;Gelinas and Nguyen 2005;Havekes et al 2012;Qian et al 2012). The induction of LTP by spike-timing-dependent plasticity protocols, where excitatory postsynaptic potentials elicited by presynaptic fiber stimulation are paired with postsynaptic action potentials evoked by current injection through an intracellular recording electrode, is also enhanced by b-AR activation (Lin et al 2003;Seol et al 2007;Makino et al 2011).…”

“…Thus, b-AR signaling complexes are crucial for both AMPAR phosphorylation and facilitation of LTP induction. The induction of LTP by TPS in the presence of ISO is also disrupted in AKAP12 mutant mice (Havekes et al 2012). Basal levels of GluA1 serine 845 phosphorylation appear to be normal in these mutants and the deficits in b-AR enhancement of LTP may stem from disruption of ERK signaling downstream of b-AR activation (Havekes et al 2012).…”

“…The induction of LTP by TPS in the presence of ISO is also disrupted in AKAP12 mutant mice (Havekes et al 2012). Basal levels of GluA1 serine 845 phosphorylation appear to be normal in these mutants and the deficits in b-AR enhancement of LTP may stem from disruption of ERK signaling downstream of b-AR activation (Havekes et al 2012). Together, these findings indicate that targeting of PKA and other signaling molecules to b-AR signaling complexes is critical for the enhancement of LTP by b-AR agonists, perhaps by providing a Perhaps the strongest evidence implicating AMPAR modulation in the mechanisms underlying b-AR enhancement of LTP comes from experiments using genetically modified mice with knock-in mutations that disrupt specific GluA1 phosphorylation sites.…”