Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson's Disease.

Motor and cognitive functions depend on the coordinated interactions between dopamine (DA) and acetylcholine (ACh) at striatal synapses. Increased ACh availability was assumed to accompany DA deficiency based on the outcome of pharmacological treatments and measurements in animals that were critically depleted of DA. Using Slc6a3 diphtheria-toxin-sensitive mice, we demonstrate that a progressive and L-dopa-responsive DA deficiency reduces ACh availability and the transcription of hyperpolarization-activated cation (HCN) channels that encode the spike timing of ACh-releasing tonically active striatal interneurons (ChIs).

Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function.

Hyperactivating mutations in the non-receptor tyrosine phosphatase SHP2 cause Noonan syndrome (NS). NS is associated with cognitive deficits, but how hyperactivation of SHP2 in NS changes neuron function is not well understood. We find that mice bearing an NS-associated SHP2 allele (NS mice) have selectively impaired Schaffer collateral-CA1 NMDA (N-methyl-D-aspartate) receptor (NMDAR)-mediated neurotransmission and that residual NMDAR-mediated currents decay faster in NS mice because of reduced contribution of GluN1:GluN2B diheteromers.

A simple end-point assay for calcium channel activity.

Cellular calcium signaling events are transient. Hence they are observed in real time using fluorescence imaging or electrophysiological methods that require sophisticated instrumentation and specialized skills. For high throughput assays simple and inexpensive techniques are desirable.

Protection of α-CaMKII from Dephosphorylation by GluN2B Subunit of NMDA Receptor Is Abolished by Mutation of Glu96 or His282 of α-CaMKII.

Interaction of CaMKII and the GluN2B subunit of NMDA receptor is essential for synaptic plasticity events such as LTP. Synaptic targeting of CaMKII and regulation of its biochemical functions result from this interaction. GluN2B binding to the T-site of CaMKII leads to changes in substrate binding and catalytic parameters and inhibition of its own dephosphorylation.

Phosphorylation status of the NR2B subunit of NMDA receptor regulates its interaction with calcium/calmodulin-dependent protein kinase II.

Ca(2+) influx through NMDA-type glutamate receptor at excitatory synapses causes activation of post-synaptic Ca(2+)/calmodulin-dependent protein kinase type II (CaMKII) and its translocation to the NR2B subunit of NMDA receptor. The major binding site for CaMKII on NR2B undergoes phosphorylation at Ser1303, in vivo. Even though some regulatory effects of this phosphorylation are known, the mode of dephosphorylation of NR2B-Ser1303 is still unclear.

Regulation of Ca2+/calmodulin-dependent protein kinase II catalysis by N-methyl-D-aspartate receptor subunit 2B.

Binding of CaMKII (Ca(2+)/calmodulin-dependent protein kinase II) to the NR2B subunit of the NMDAR (N-methyl-D-aspartate-type glutamate receptor) in the PSD (postsynaptic density) is essential for the induction of long-term potentiation. In this study, we show that binding of NR2B to the T-site (Thr(286)-autophosphorylation site binding pocket) of CaMKII regulates its catalysis as reflected in the kinetic parameters. The apparent S(0.