GABAB Receptor Subunit GB1 at the Cell Surface Independently Activates ERK1/2 through IGF-1R Transactivation

BACKGROUND: Functional GABA(B) receptor is believed to require hetero-dimerization between GABA(B1) (GB1) and GABA(B2) (GB2) subunits. The GB1 extracellular domain is required for ligand binding, and the GB2 trans-membrane domain is responsible for coupling to G proteins. Atypical GABA(B) receptor responses observed in GB2-deficient mice suggested that GB1 may have activity in the absence of GB2. However the underlying mechanisms remain poorly characterized. METHODOLOGY/PRINCIPAL FINDINGS: Here, by using cells overexpressing a GB1 mutant (GB1asa) with the ability to translocate to the cell surface in the absence of GB2, we show that GABA(B) receptor agonists, such as GABA and Baclofen, can induce ERK1/2 phosphorylation in the absence of GB2. Furthermore, we demonstrate that GB1asa induces ERK1/2 phosphorylation through Gi/o proteins and PLC dependent IGF-1R transactivation. CONCLUSIONS/SIGNIFICANCE: Our data suggest that GB1 may form a functional receptor at the cell surface in the absence of GB2

Phosphorylation of AMPA Receptors Is Required for Sensory Deprivation-Induced Homeostatic Synaptic Plasticity

Sensory experience, and the lack thereof, can alter the function of excitatory synapses in the primary sensory cortices. Recent evidence suggests that changes in sensory experience can regulate the synaptic level of Ca2+-permeable AMPA receptors (CP-AMPARs). However, the molecular mechanisms underlying such a process have not been determined. We found that binocular visual deprivation, which is a well-established in vivo model to produce multiplicative synaptic scaling in visual cortex of juvenile rodents, is accompanied by an increase in the phosphorylation of AMPAR GluR1 (or GluA1) subunit at the serine 845 (S845) site and the appearance of CP-AMPARs at synapses. To address the role of GluR1-S845 in visual deprivation-induced homeostatic synaptic plasticity, we used mice lacking key phosphorylation sites on the GluR1 subunit. We found that mice specifically lacking the GluR1-S845 site (GluR1-S845A mutants), which is a substrate of cAMP-dependent kinase (PKA), show abnormal basal excitatory synaptic transmission and lack visual deprivation-induced homeostatic synaptic plasticity. We also found evidence that increasing GluR1-S845 phosphorylation alone is not sufficient to produce normal multiplicative synaptic scaling. Our study provides concrete evidence that a GluR1 dependent mechanism, especially S845 phosphorylation, is a necessary pre-requisite step for in vivo homeostatic synaptic plasticity

A prospective study of changes in anxiety, depression, and problems in living during chemotherapy treatments: effects of age and gender

PurposeMonitoring distress assessment in cancer patients during the treatment phase is a component of good quality care practice. Yet, there is a dearth of prospective studies examining distress. In an attempt to begin filling this gap and inform clinical practice, we conducted a prospective, longitudinal study examining changes in distress (anxiety, depression, and problems in living) by age and gender and the roles of age and gender in predicting distress.MethodsNewly diagnosed Brazilian cancer patients (N = 548) were assessed at three time points during chemotherapy. Age and gender were identified on the first day of chemotherapy (T1); anxiety, depression, and problems in living were self-reported at T1, the planned midway point (T2), and the last day of chemotherapy (T3).ResultsAt T1, 37 and 17% of patients reported clinically significant levels of anxiety and depression, respectively. At T3, the prevalence was reduced to 4.6% for anxiety and 5.1% for depression (p < .001). Patients 40-55 years, across all time points, reported greater anxiety and practical problems than patients >70 years (p < .03). Female patients reported greater emotional, physical, and family problems than their male counterparts (p < .04).ConclusionsFor most patients, elevated levels of distress noted in the beginning of treatment subsided by the time of treatment completion. However, middle-aged and female patients continued to report heightened distress. Evidence-based psychosocial intervention offered to at risk patients during early phases of the treatment may provide distress relief and improve outcomes over the illness trajectory while preventing psychosocial and physical morbidity due to untreated chronic distress