Nischarin as a functional imidazoline (I₁) receptor

Abstract

Gene matching shows that Nischarin is a mouse homologue of human imidazoline receptor antisera-selective (IRAS) protein, a viable candidate of the imidazoline (I 1 ) receptor. Nischarin and IRAS share the functions of enhancing cell survival, growth and migration. Bioinformatics modeling indicates that the IRAS and Nischarin may be transmembrane proteins and the convergence information raises the interesting possibility that Nischarin might serve as the I 1 -receptor. To test this hypothesis, we developed antibodies against the Nischarin protein, and conducted signal transduction (functional) studies with the I 1 -receptor agonist rilmenidine in the presence and absence of Nischarin antisense oligodeoxynucleotides (ODNs). NIH3T3 cells transfected with the Nischarin cDNA and incubated with the newly synthesized antibody expressed a 190 kD band. The antibody identified endogenous Nischarin in differentiated PC12 cells around 210 kD, which is consistent with reported findings in other cells of neuronal origin. The immunoflourescence findings showed the targeted protein to be associated with the cell membrane in PC12 cells. Nischarin ODNs abolished the expression of Nischarin in PC12 cells. Equally important, the Nischarin ODNs eliminated the production of MAPK p42/44 , a recognized signal transduction product generated by I 1 -receptor activation in differentiated PC12 cells. Together, the present findings suggest that Nischarin may serve as the functional I 1 -receptor or at least share a common signaling pathway in the differentiated PC12 cells.

Platelet imidazoline receptors as state marker of depressive symptomatology

“…The IR-1 protein has been associated with IRAS (Li et al, 2006;Zhang & Abdel-Rahman, 2006), a membrane-linked protein without similarity to G-protein coupled receptors (Plletz et al, 2000). IRAS interacts with a number of membranous receptors, such as the mu-opioid receptor, of relevance to mood disorders Piletz et al, 2000a;Wu et al, 2005).…”

Inhibition of Nischarin Expression Attenuates Rilmenidine-Evoked Hypotension and Phosphorylated Extracellular Signal-Regulated Kinase 1/2 Production in the Rostral Ventrolateral Medulla of Rats

“…Our recent findings in rat pheochromocytoma (PC12) cells (Zhang and Abdel-Rahman, 2006), supported by a subsequent study in the same cell line (Sun et al, 2007), suggest that nischarin serves as, or at least shares, a common signaling pathway with the I 1 R. Nischarin was first identified as a mouse homolog of human IRAS (Alahari et al, 2000;Alahari, 2003). It is noteworthy that human IRAS has been considered the I 1 R since the transfection of IRAS cDNA into the Chinese hamster ovary cells led to the expression of highaffinity I 1 binding sites for moxonidine and rilmenidine (Piletz et al, 2000).…”

Novel I1-imidazoline S43126 enhance insulin action in PC12 cells

“…Similarly, PC12 cells transfected with cDNA encoding nischarin, increased I 1 R binding sites as shown by radioligand binding studies. Nischarin antisense abolished both expression of protein as well as substantially reduced the generation of ERK elicited by I 1 R agonist [27]. Molderings and colleagues conducted radioligand binding experiments with clonidine and moxonidine in PC12 cells and concluded that I 1 R represented a mixture of S1P1/S1P3-receptor hetero-dimers [20].…”

“…Similar to our findings, nischarin antisense oligodeoxynucleotide (ODN) abolished the expression of nischarin in PC12 cells. Moreover, nischarin ODN eliminated the phosphorylation of ERK1/2 elicited by another I 1 -imidazoline agonist, rilmenidine, in PC12 cells [27]. Additional experiments were done using lower concentrations of S43126 (10 -9 M) in combination with varying doses of insulin (10 -9 -10 -5 M) and also using insulin (10 -9 M) with varying doses of S43126 (10 -9 -10 -5 M).…”

“…Nischarin, is the truncated form (PX domain missing) of mouse IRAS, and nischarin antisense oligodeoxynucleotide was shown to abolish the expression of nischarin and eliminated the production of ERK1/2 in PC12 cells following treatment by rilmenidine, an I R agonist [27].…”