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Voltage-and store-operated calcium ([Ca.sup.2+]) channels are the major routes of [Ca.sup.2+] entry in mammalian cells, but little is known about how cells coordinate the activity of these channels to generate coherent calcium signals. We found that STIM1 (stromal interaction molecule 1), the main activator of store-operated [Ca.sup.2+] channels, directly suppresses depolarization-induced opening of the voltage-gated [Ca.sup.2+] channel [Ca.sub.v]1.2. STIM1 binds to the C terminus of [Ca.sub.v]1.2 through its [Ca.sup.2+] release-activated [Ca.sup.2+] activation domain, acutely inhibits gating, and causes long-term internalization of the channel from the membrane. This establishes a previously unknown function for STIM1 and provides a molecular mechanism to explain the reciprocal regulation of these two channels in cells. 10.1126/science.1191027

Increases in the intracellular concentration of calcium ([[[Ca.sup.2+]].sub.i]) activate various signaling pathways that lead to the expression of genes that are essential for dendritic development, neuronal survival, and synaptic plasticity. The mode of [Ca.sup.2+] entry into a neuron plays a key role in determining which signaling pathways are activated and thus specifies the cellular response to [Ca.sup.2+]. [Ca.sup.2+] influx through L-type voltage-activated channels (LTCs) is particularly effective at activating transcription factors such as CREB and MEF-2. We developed a functional knock-in technique to investigate the features of LTCs that specifically couple them to the signaling pathways that regulate gene expression. We found that an isoleucine-glutamine ('IQ') motif in the carboxyl terminus of the LTC that binds [Ca.sup.2+]-calmodulin (CaM) is critical for conveying the [Ca.sup.2+] signal to the nucleus. [Ca.sup.2+]-CaM binding to the LTC was necessary for activation of the Ras/mitogen-activated protein kinase (MAPK) pathway, which conveys local [Ca.sup.2+] signals from the mouth of the LTC to the nucleus. CaM functions as a local [Ca.sup.2+] sensor at the mouth of the LTC that activates the MAPK pathway and leads to the stimulation of genes that are essential for neuronal survival and plasticity., Voltage-gated [Ca.sup.2+] channels have a central role in neuronal function and are essential for converting electrical activity into biochemical events (1). Neurons express at least nine types of voltage-gated [Ca.sup.2+] [...]

SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)--mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56β, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient--derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency. [ABSTRACT FROM AUTHOR]

Changes in the concentration of intracellular Ca2+ ([Ca2+]i) in response to various stimuli play a role in regulating numerous cellular processes, including the activation of gene expression. In neurons, the extraordinary diversity of the response to Ca2+ signaling depends on the location, intensity, and duration of the Ca2+ transient. Interestingly, Ca2+-dependent gene transcription appears to be sensitive both to increases in nuclear Ca2+, which occur after relatively intense stimuli, and to highly localized increases in Ca2+ near the sites of Ca2+ influx. Activation of intracellular signaling pathways by specific types of Ca2+ channels depends on localization of specific Ca2+ receptors close to the channel mouth. The dual regulation of signaling pathways by Ca2+ near channels and in the nucleus may permit neurons to precisely tailor transcriptional activation to specific types of electrical or chemical stimuli and at the same time ensure that only robust stimuli that generate nuclear Ca2+ elevations are converted into long-term changes in gene expression.