Protein interacting with C kinase and neurological disorders.

Best known for its interaction with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit GluA2 and for its influence on excitatory synapse activity, the protein interacting with C kinase, PICK1, is the focus of considerable attention from neurobiologists. Indeed, this PSD-95/DlgA/ZO-1 (PDZ) domain-containing protein has been shown to interact with a wide variety of neurotransmitter receptors, transporters, and enzymes, including glutamate and nicotinic acetylcholine receptors, dopamine and glutamate transporters, and the enzyme serine racemase. Through its lipid binding domain, PICK1 is targeted to the inner surface of the cell membrane where it contributes to anchoring these partners and thereby influences their synaptic localization and function.

Increasing the density of the D2L receptor and manipulating the receptor environment are required to evidence the partial agonist properties of aripiprazole.

The clinical efficacy of aripiprazole in the treatment of psychosis relies on a partial agonism at D2 receptors. As the expression of this receptor differs physiologically between pre- and post-synaptic sites and is affected by pathological conditions or pharmacological treatments, it appears difficult to predict the clinical response to partial agonists. In addition, the response to this novel antipsychotic was shown to depend on the cell-line and the pathway analyzed, suggesting a functional selective profile at the D2 receptor.

The VPAC2 agonist peptide histidine isoleucine (PHI) up-regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1G93A) by inhibiting caspase-3 mediated inactivation of GLT-1a.

Degeneration of corpus callosum appears in patients with amyotrophic lateral sclerosis (ALS) before clinical signs of upper motor neuron death. Considering the ALS-associated impairment of astrocytic glutamate uptake, we have characterized the expression and activity of the glutamate transporter isoforms GLT-1a and GLT-1b in the corpus callosum of transgenic rats expressing a mutated form of the human superoxide dismutase 1 (hSOD1(G93A)). We have also studied the effect of peptide histidine isoleucine (PHI), a vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 2 (VPAC(2)) agonist on glutamate transporters both in vivo and in callosal astrocytes.

Differential regulation of C-terminal splice variants of the glutamate transporter GLT-1 by tumor necrosis factor-alpha in primary cultures of astrocytes.

The high-affinity glutamate transporter GLT-1 plays a key role in the control of the glutamate homeostasis in the central nervous system and protects neurons against excitotoxicity. Splice variants of the original transcript have been identified and their involvement in neurodegenerative disorders has been proposed. However, the functions and the regulations of these isoforms remain unclear.