Showing papers by "Michael J. Berridge published in 2014"

Calcium regulation of neural rhythms, memory and Alzheimer's disease

Abstract: Alzheimer's disease (AD) begins with a decline in cognition followed by neuronal cell death and dementia. These changes have been linked to a deregulation of Ca2+ signalling caused by a progressive increase in the resting level of Ca2+, which may influence cognition by interfering with the rhythm rheostat that controls the sleep/wake cycle. The rise in resting levels of Ca2+ may not alter the processes of memory acquisition during consciousness (gamma and theta rhythms), but may duplicate some of the events that occur during the slow oscillations responsible for the twin processes of memory consolidation and memory erasure that occur during sleep. The persistent elevation in the resting level of Ca2+ induced by an accumulation of amyloid β (Aβ) oligomers duplicates a similar small global elevation normally restricted to the period of slow oscillations when memories are erased during sleep. In AD, such a rapid erasure of memories soon after they are acquired during the wake period means that they are not retained for consolidation during sleep. The Aβ deregulates Ca2+ signalling through direct effects on the neurons and indirectly by inducing inflammatory responses in the microglia and astrocytes. Some of these deleterious effects of Aβ may be alleviated by vitamin D.

Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia

Abstract: Neurons have highly developed Ca2+ signalling systems responsible for regulating many neural functions such as the generation of brain rhythms, information processing and the changes in synaptic plasticity that underpins learning and memory. The signalling mechanisms that regulate neuronal excitability are particularly important for processes such as sensory perception, cognition and consciousness. The Ca2+ signalling pathway is a key component of the mechanisms responsible for regulating neuronal excitability, information processing and cognition. Alterations in gene transcription are particularly important as they result in subtle alterations in the neuronal signalling mechanisms that have been implicated in many neural diseases. In particular, dysregulation of the Ca2+ signalling pathway has been implicated in the development of some of the major psychiatric diseases such as bipolar disorder (BPD) and schizophrenia.

Feedback regulation mediated by Bcl-2 and DARPP-32 regulates inositol 1,4,5-trisphosphate receptor phosphorylation and promotes cell survival

Abstract: Bcl-2 interacts with the inositol 1,4,5-trisphosphate receptor (InsP3R) and thus prevents InsP3-induced Ca(2+) elevation that induces apoptosis. Here we report that Bcl-2 binds dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), a protein kinase A (PKA)-activated and calcineurin (CaN)-deactivated inhibitor of protein phosphatase 1 (PP1). Bcl-2 docks DARPP-32 and CaN in a complex on the InsP3R, creating a negative feedback loop that prevents exaggerated Ca(2+) release by decreasing PKA-mediated InsP3R phosphorylation. T-cell activation increases PKA activity, phosphorylating both the InsP3R and DARPP-32. Phosphorylated DARPP-32 inhibits PP1, enhancing InsP3R phosphorylation and Ca(2+) release. Elevated Ca(2+) activates CaN, which dephosphorylates DARPP-32 to dampen Ca(2+) release by eliminating PP1 inhibition to enable it to dephosphorylate the InsP3R. Knocking down either Bcl-2 or DARPP-32 abrogates this feedback mechanism, resulting in increased Ca(2+) elevation and apoptosis. This feedback mechanism appears to be exploited by high levels of Bcl-2 in chronic lymphocytic leukemia cells, repressing B-cell receptor-induced Ca(2+) elevation and apoptosis.