A new specific neuronal modulatory effect of nicotine: the functional cross talk between nicotinic and glutamate receptors

We here have addressed the topic of the cross-talk between receptors. We provide evidence supporting the co-localization and the functional interaction between nicotinic acetylcholine receptors and some glutamatergic receptors. The recruitment of nicotinic acetylcholine receptors dynamically and negatively modulates the function of both N-methyl-D-aspartic acid (NMDA) and ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors throughout their selective internalization. This dynamic control by cholinergic nicotinic system of NMDA and ?-AMPA receptors is operative even at very low concentrations of nicotine. Nicotinic and glutamatergic receptors have been both implicated in important neurological and psychiatric disorders such as Alzheimer’s and Parkinson’s disease, schizophrenia, and anxiety. Thus, a more extensive and detailed knowledge of this new modulatory role of nicotine may eventually enable us to develop specific therapeutic interventions for these pathologies

Presynaptic c-Jun N-terminal Kinase 2 regulates NMDA receptor-dependent glutamate release

Activation of c-Jun N-terminal kinase (JNK) signaling pathway is a critical step for neuronal death occurring in several neurological conditions. JNKs can be activated via receptor tyrosine kinases, cytokine receptors, G-protein coupled receptors and ligand-gated ion channels, including the NMDA glutamate receptors. While JNK has been generally associated with postsynaptic NMDA receptors, its presynaptic role remains largely unexplored. Here, by means of biochemical, morphological and functional approaches, we demonstrate that JNK and its scaffold protein JIP1 are also expressed at the presynaptic level and that the NMDA-evoked glutamate release is controlled by presynaptic JNK-JIP1 interaction. Moreover, using knockout mice for single JNK isoforms, we proved that JNK2 is the essential isoform in mediating this presynaptic event. Overall the present findings unveil a novel JNK2 localization and function, which is likely to play a role in different physiological and pathological conditions

A new specific neuronal modulatory effect of nicotine: the functional cross talk between nicotinic and glutamate receptors

We here have addressed the topic of the cross-talk between receptors. We provide evidence supporting the co-localization and the functional interaction between nicotinic acetylcholine receptors and some glutamatergic receptors. The recruitment of nicotinic acetylcholine receptors dynamically and negatively modulates the function of both N-methyl-D-aspartic acid (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors throughout their selective internalization. This dynamic control by cholinergic nicotinic system of NMDA and α-AMPA receptors is operative even at very low concentrations of nicotine. Nicotinic and glutamatergic receptors have been both implicated in important neurological and psychiatric disorders such as Alzheimer’s and Parkinson’s disease, schizophrenia, and anxiety. Thus, a more extensive and detailed knowledge of this new modulatory role of nicotine may eventually enable us to develop specific therapeutic interventions for these pathologies

Nicotinic modulation of glutamate receptor function at nerve terminal level: a fine-tuning of synaptic signals

This review focuses on a specific interaction occurring between the nicotinic cholinergic receptors (nAChRs) and the glutamatergic receptors (GluRs) at the nerve endings level. We have employed synaptosomes in superfusion and supplemented and integrated our findings with data obtained using techniques from molecular biology and immuno-cytochemistry, and the assessment of receptor trafficking. In particular, we characterize the following: (1) the direct and unequivocal localization of native \u3b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamatergic receptors on specific nerve terminals, (2) their pharmacological characterization and functional co-localization with nAChRs on the same nerve endings, and (3) the existence of synergistic or antagonistic interactions among them. Indeed, in the rat nucleus accumbens (NAc), the function of some AMPA and NMDA receptors present on the dopaminergic and glutamatergic nerve terminals can be regulated negatively or positively in response to a brief activation of nAChRs. This effect occurs rapidly and involves the trafficking of AMPA and NMDA receptors. The event takes place also at very low concentrations of nicotine and involves the activation of several nAChRs subtypes. This dynamic control by cholinergic nicotinic system of glutamatergic NMDA and AMPA receptors might therefore represent an important neuronal presynaptic adaptation associated with nicotine administration. The understanding of the role of these nicotine-induced functional changes might open new and interesting perspectives both in terms of explaining the mechanisms that underlie some of the effects of nicotine addiction and in the development of new drugs for smoking cessation

Metamodulation of presynaptic NMDA receptors: New perspectives for pharmacological interventions

: Metamodulation shifted the scenario of the central neuromodulation from a simplified unimodal model to a multimodal one. It involves different receptors/membrane proteins physically associated or merely colocalized that act in concert to control the neuronal functions influencing each other. Defects or maladaptation of metamodulation would subserve neuropsychiatric disorders or even synaptic adaptations relevant to drug dependence. Therefore, this "vulnerability" represents a main issue to be deeply analyzed to predict its aetiopathogenesis, but also to propose targeted pharmaceutical interventions. The review focusses on presynaptic release-regulating NMDA receptors and on some of the mechanisms of their metamodulation described in the literature. Attention is paid to the interactors, including both ionotropic and metabotropic receptors, transporters and intracellular proteins, which metamodulate their responsiveness in physiological conditions but also undergo adaptation that are relevant to neurological dysfunctions. All these structures are attracting more and more the interest as promising druggable targets for the treatment of NMDAR-related central diseases: these substances would not exert on-off control of the colocalized NMDA receptors (as usually observed with NMDAR full agonists/antagonists), but rather modulate their functions, with the promise of limiting side effects that would favor their translation from preclinic to clinic