Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin

Abstract

The noradrenergic system in the prefrontal cortex (PFC) is involved in many physiological and psychological processes, including working memory and mood control. To understand the functions of the noradrenergic system, we examined the regulation of NMDA receptors (NMDARs), key players in cognition and emotion, by ␣1-and ␣2-adrenergic receptors (␣1-ARs, ␣2-ARs) in PFC pyramidal neurons. Applying norepinephrine or a norepinephrine transporter inhibitor reduced the amplitude but not paired-pulse ratio of NMDAR-mediated excitatory postsynaptic currents (EPSC) in PFC slices. Specific ␣1-AR or ␣2-AR agonists also decreased NMDAR-EPSC amplitude and whole-cell NMDAR current amplitude in dissociated PFC neurons. The ␣1-AR effect depended on the phospholipase C-inositol 1,4,5-trisphosphate-Ca 2؉ pathway, whereas the ␣2-AR effect depended on protein kinase A and the microtubule-based transport of NMDARs that is regulated by ERK signaling. Furthermore, two members of the RGS family, RGS2 and RGS4, were found to down-regulate the effect of ␣1-AR on NMDAR currents, whereas only RGS4 was involved in inhibiting ␣2-AR regulation of NMDAR currents. The regulating effects of RGS2/4 on ␣1-AR signaling were lost in mutant mice lacking spinophilin, which binds several RGS members and G protein-coupled receptors, whereas the effect of RGS4 on ␣2-AR signaling was not altered in spinophilin-knockout mice. Our work suggests that activation of ␣1-ARs or ␣2-ARs suppresses NMDAR currents in PFC neurons by distinct mechanisms. The effect of ␣1-ARs is modified by RGS2/4 that are recruited to the receptor complex by spinophilin, whereas the effect of ␣2-ARs is modified by RGS4 independent of spinophilin.A drenergic receptors (ARs) can be divided into three main types: ␣1 (␣ 1A-D ), ␣2 (␣ 2A-C ), and ␤ (1-3), based on sequence information, receptor pharmacology, and signaling mechanisms. Although ␤-ARs are located mainly in the cardiovascular system, most ␣1-and ␣2-AR subtypes (except ␣ 1C and ␣ 2B ) are highly expressed in CNS regions, e.g., prefrontal cortex (PFC), hippocampus, and brainstem. Norepinephrine, through the action of ␣1-ARs and ␣2-ARs, has been implicated in many key functions of PFC, including working memory and emotional control (1-3). An aberrant noradrenergic system, complementing altered serotonergic or dopaminergic signaling, contributes significantly to the pathophysiology of a variety of neuropsychiatric diseases associated with PFC dysfunction, such as depression, anxiety, schizophrenia, and attention-deficit hyperactivity disorder (4-7). Therefore, modifying noradrenergic signaling has been considered one of the key therapeutic actions of many antidepressants, anxiolytic drugs, and antipsychotics (8, 9). To understand the functional role of ␣1-and ␣2-ARs, we need to know their cellular targets that are important for cognition and emotion. The NMDAR channel has been implicated in normal cognitive processes and mental disorders (10-12), which makes it a potentially important target by which ␣1-and ␣2-ARs may regulate PFC ...

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

“…Thus, Rgs4 shows complex brain region-, context-, and treatment-specific regulation, consistent with its modulation of numerous GPCRs, including several adrenergic, dopaminergic, serotonergic, opiate, muscarinic, and metabotropic glutamate receptors (mGluRs), which are either Gαi or Gαq coupled (2-9, 31, 32). Further work is needed to understand the complex interactions between Rgs4 and several other signaling proteins that control receptor function (2,8,9,18,30,31) and how these mechanisms influence therapeutic-like responses to monoamine-based antidepressant medications.…”

“…Regulator of G protein signaling 4 (Rgs4) is a 28-kDa protein known to control postreceptor signaling cascades for numerous G protein-coupled receptors (GPCRs), including dopamine, serotonin, adrenergic, muscarinic, and mu and delta opioid receptors (2)(3)(4)(5)(6)(7)(8)(9). Rgs4 is generally thought to be a negative modulator of Gα subunits by promoting their hydrolysis of GTP and by antagonizing the regulation of their effectors, although the actions of Rgs proteins are more complex, because they can either inhibit or facilitate several actions of their associated receptors (10,11).…”

Effects of midazolam on acquisition and extinction of conditioned taste aversion memory in rats

“…In the previous paper [15], we reported that subhypnotic but not hypnotic doses of propofol, one of non-benzodiazepine anesthetic agents, which has GABA-potentiating properties [12,23,25] In the present study, we examined the effect of anesthetics applied between CS and US presentations on the long-term CTAM using several dosages of benzodiazepine agent, midazolam and compared the effects of midazolam with those of non-benzodiazepine, propofol. Furthermore, noradrenergic system has been reported to play an important role in the memory retention [7,18,19]. Therefore, we examined the effect of yohimbin , an α2 adrenoceptor antagonist on acquisition and retention of CTAM.…”

“…Midazolam also represented optimal concentration in acceleration effect on extinction of CTAM (Fig.2). However, tendency for midazolam to suppress the AI was observed, and post CS-injection of 613 µM midazolam significantly suppressed the AI.Midazolam generated the optimal suppression of RI at higher concentration (75 µM) than propofol (14 µM) [15], while midazolam represented steeper dose-response relationship than propofol.Recently, noradrenergic system has been reported to play an important role in the memory retention [7,18,19]. Therefore, we attempted to apply 1 mg/kg yohimbin, anα2 adrenoceptor antagonist, instead of anesthetics.…”

“…Recently, noradrenergic system has been reported to play an important role in the memory retention [7,18,19]. Therefore, we attempted to apply 1 mg/kg yohimbin, anα2 adrenoceptor antagonist, instead of anesthetics.…”