Presynaptic External Calcium Signaling Involves the Calcium-Sensing Receptor in Neocortical Nerve Terminals

Nerve terminal invasion by an axonal spike activates voltage-gated channels, triggering calcium entry, vesicle fusion, and release of neurotransmitter. Ion channels activated at the terminal shape the presynaptic spike and so regulate the magnitude and duration of calcium entry. Consequently characterization of the functional properties of ion channels at nerve terminals is crucial to understand the regulation of transmitter release. Direct recordings from small neocortical nerve terminals have revealed that external [Ca(2+)] ([Ca(2+)](o)) indirectly regulates a non-selective cation channel (NSCC) in neocortical nerve terminals via an unknown [Ca(2+)](o) sensor. Here, we identify the first component in a presynaptic calcium signaling pathway.By combining genetic and pharmacological approaches with direct patch-clamp recordings from small acutely isolated neocortical nerve terminals we identify the extracellular calcium sensor. Our results show that the calcium-sensing receptor (CaSR), a previously identified G-protein coupled receptor that is the mainstay in serum calcium homeostasis, is the extracellular calcium sensor in these acutely dissociated nerve terminals. The NSCC currents from reduced function mutant CaSR mice were less sensitive to changes in [Ca(2+)](o) than wild-type. Calindol, an allosteric CaSR agonist, reduced NSCC currents in direct terminal recordings in a dose-dependent and reversible manner. In contrast, glutamate and GABA did not affect the NSCC currents.Our experiments identify CaSR as the first component in the [Ca(2+)](o) sensor-NSCC signaling pathway in neocortical terminals. Decreases in [Ca(2+)](o) will depress synaptic transmission because of the exquisite sensitivity of transmitter release to [Ca(2+)](o) following its entry via voltage-activated Ca(2+) channels. CaSR may detects such falls in [Ca(2+)](o) and increase action potential duration by increasing NSCC activity, thereby attenuating the impact of decreases in [Ca(2+)](o) on release probability. CaSR is positioned to detect the dynamic changes of [Ca(2+)](o) and provide presynaptic feedback that will alter brain excitability

Antipsychotic drugs upregulate lipogenic gene expression by disrupting intracellular trafficking of lipoprotein-derived cholesterol

Antipsychotic drugs (APDs) have been reported to induce lipogenic genes. This has been proposed to contribute to their efficacy in treating schizophrenia and other psychiatric disorders, as well as the metabolic side effects often associated with these drugs. The precise mechanism for the lipogenic effects of APDs is unknown, but is believed to involve increased activation of the lipogenic transcription factors, such as sterol regulatory element binding proteins (SREBPs). In a series of experiments in a model cell line, we found that a panel of typical and atypical APDs inhibited transport of lipoprotein-derived cholesterol to the endoplasmic reticulum (ER), which houses the cholesterol homeostatic machinery. APDs belong to the class of cationic amphiphiles and as has been shown for other amphiphiles, caused lipoprotein-derived cholesterol to accumulate intracellularly, preventing it from being esterified in the ER and suppressing SREBP activation. APDs did not activate the liver X receptor, another transcription factor involved in lipogenesis. However, these drugs markedly reduced cholesterol synthesis. This paradoxical result indicates that the upregulation of SREBP-target genes by APDs may not translate to increased cellular cholesterol levels. In conclusion, we have determined that APDs disrupt intracellular trafficking and synthesis of cholesterol, which may have important clinical ramifications. © 2010 Macmillan Publishers Limited. All rights reserved