Adrenaline Stimulates Glucagon Secretion by Tpc2-Dependent Ca2+ Mobilization From Acidic Stores in Pancreatic α-Cells.

Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of ß-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline in mouse and human α-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity, and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+]i in α-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+]i in α-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca2+]i Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that ß-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+]i signaling in the α-cell that is initiated by cAMP-induced Tpc2-dependent Ca2+ release from the acidic stores and further amplified by Ca2+-induced Ca2+ release from the sarco/endoplasmic reticulum.

Variation in blood pressure is associated with white matter microstructure but not cognition in African Americans.

Although hypertension is a major risk factor for cerebrovascular disease (CVD) and is highly prevalent in African Americans, little is known about how blood pressure (BP) affects brain-behavior relationships in this population. In predominantly Caucasian populations, high BP is associated with alterations in frontal-subcortical white matter and in executive functioning aspects of cognition. We investigated associations among BP, brain structure, and neuropsychological functioning in 52 middle-older-age African Americans without diagnosed history of CVD. All participants underwent diffusion tensor imaging for examination of white matter integrity, indexed by fractional anisotropy (FA). Three regions of interest were derived in the anterior (genu) and posterior (splenium) corpus callosum and across the whole brain. A brief neuropsychological battery was administered from which composite scores of executive function and memory were derived. Blood pressure was characterized by mean arterial blood pressure (MABP). When controlling for age, higher MABP was associated with lower FA in the genu, and there was a trend for this same relationship with regard to whole-brain FA. When the sample was broken into groups on the basis of treatment for BP regulation (medicated vs. nonmedicated), MABP was related to genu and whole-brain FA only in the nonmedicated group. Neither MABP nor FA was significantly related to either neuropsychological composite score regardless of medication use. These data provide important evidence that variation in BP may contribute to significant alterations in specific neural regions of white matter in nonmedicated individuals without symptoms of overt CVD.

Basal ganglia-thalamocortical circuitry disruptions in schizophrenia during delayed response tasks.

BACKGROUND: Schizophrenia is characterized by executive functioning deficits, presumably mediated by prefrontal cortex dysfunction. For example, schizophrenia participants show performance deficits on ocular motor delayed response (ODR) tasks, which require both inhibition and spatial working memory for correct performance. METHODS: The present functional magnetic resonance imaging (fMRI) study compared neural activity of 14 schizophrenia and 14 normal participants while they performed ODR tasks. RESULTS: Schizophrenia participants generated: 1) more trials with anticipatory saccades (saccades made during the delay period), 2) memory saccades with longer latencies, and 3) memory saccades of decreased accuracy. Increased blood oxygenation level-dependent (BOLD) signal changes were observed in both groups in ocular motor circuitry (e.g., supplementary eye fields [SEF], lateral frontal eye fields [FEF], inferior parietal lobule [IPL], cuneus, and precuneus). The normal, but not the schizophrenia, group demonstrated BOLD signal changes in dorsolateral prefrontal regions (right Brodmann area [BA] 9 and bilateral BA 10), medial FEF, insula, thalamus, and basal ganglia. Correlations between percentage of anticipatory saccade trials and BOLD signal changes were more similar between groups for subcortical regions and less similar for cortical regions. CONCLUSIONS: These results suggest that executive functioning deficits in schizophrenia may be associated with dysfunction of the basal ganglia-thalamocortical circuitry, evidenced by decreased prefrontal cortex, basal ganglia, and thalamus activity in the schizophrenia group during ODR task performance.