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Carbon monoxide (CO) synthesized by heme oxygenase 2 (HO2) and nitric oxide (NO) produced by neuronal NO synthase (nNOS) mediate nonadrenergic/noncholinergic (NANC) intestinal relaxation. In many areas of the gastrointestinal tract, NO and CO function as coneurotransmitters. In the internal anal sphincter (IAS), NANC relaxation is mediated primarily by CO. Vasoactive intestinal polypeptide (VIP) has also been shown to participate in NANC relaxation throughout the intestine, including the IAS. By using a combination of pharmacology and genetic knockout of the biosynthetic enzymes for CO and NO, we show that the physiologic effects of exogenous and endogenous VIP in the IAS are mediated by HO2-synthesized CO.

The immunophilin FK506 binding protein 12 (FKBP12) forms physiological complexes with purified inositol 1,4,5-trisphosphate receptor (IP3R), an intracellular Ca2+ release channel, to regulate Ca2+ flux. Addition of FKBP12 reverses the increase of Ca2+ flux through IP3R caused upon disruption of interaction between IP3R and FKBP12. FKBP12 also regulates the Ca2+ conductance of IP3R. Immunosuppressants FK506 and rapamycin that bind FKBP12 with high affinity, disrupt the complex of IP3R and FKBP12.

NADH regulates the release of calcium from the endoplasmic reticulum by modulation of inositol 1,4,5-trisphosphate receptors (I[P.sub.3]R), accounting for the augmented calcium release of hypoxic cells. We report selective binding of I[P.sub.3]R to GAPDH, whose activity leads to the local generation of NADH to regulate intracellular calcium signaling. This interaction requires cysteines 992 and 995 of I[P.sub.3]R and C150 of GAPDH. Addition of native GAPDH and NA[D.sup.+] to WT I[P.sub.3]R stimulates calcium release, whereas no stimulation occurs with C992S/995S I[P.sub.3]R that cannot bind GAPDH. Thus, the I[P.sub.3]R/ GAPDH interaction likely enables cellular energy dynamics to impact calcium signaling. calcium | hypoxia | metabolism

Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function. [ABSTRACT FROM AUTHOR]

NADH regulates the release of calcium from the endoplasmic reticulum by modulation of inositol 1,4,5-trisphosphate receptors (IP3R), accounting for the augmented calcium release of hypoxic cells. We report selective binding of IP3R to GAPDH, whose activity leads to the local generation of NADH to regulate intracellular calcium signaling. This interaction requires cysteines 992 and 995 of IP3R and C150 of GAPDH. Addition of native GAPDH and NAD+ to WT IP3R stimulates calcium release, whereas no stimulation occurs with C992S/995S IP3R that cannot bind GAPDH. Thus, the IP3R/ GAPDH interaction likely enables cellular energy dynamics to impact calcium signaling. [ABSTRACT FROM AUTHOR]