Disease relevance of Gc

• In the current study, a cDNA to rat DBP mRNA was cloned from a bacteriophage lambda gt 11 rat liver expression library [1].
• Alterations in plasma levels and complexing of Gc (vitamin D-binding protein) in rats with endotoxic shock [2].
• Since complexing with G-actin displaces fatty acids, possible alterations in plasma levels of Gc and extent of complexing were sought in serial samples obtained from rats with shock induced by Salmonella enteritidis endotoxin (12.5-15 mg kg-1) [2].
• NGF treatment prevented the withdrawal-associated loss, and induced hypertrophy, of cholinergic neurons.These findings show that exogenous NGF protects the phenotype and prevents the withdrawal-induced degeneration of cholinergic neurons in the MS/VDB [3].

Psychiatry related information on Gc

• These experiments suggest that excitotoxic lesions of the septum/VDB produce deficits in conditional discrimination learning and performance, and that the integrity of the projection to the cingulate cortex is more crucial than that to the hippocampus in this effect [4].
• Neither lesion affected simple visual or spatial discrimination or reversal learning, also carried out in operant chambers, but both significantly impaired the acquisition and retention of a spatial navigation task (Morris water maze), with the septal/VDB lesions again producing greater deficits than the hippocampal lesions [5].
• These results indicate state-specific effects on transcription and subsequent protein expression in cell populations associated with behavioral state and further show that the HDB, VDB and VLPO are good candidates for the further study of intracellular events associated with sleep and wakefulness [6].
• Following AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) lesions of the vertical limb diagonal band of Broca (VDB) which provides the main cholinergic projection to cingulate cortex, animals were not significantly impaired on the 5-choice serial reaction time task [7].
• Burst firing neurons of the medial septal area (MS/VDB) are thought to pace the HPC theta rhythm during REM sleep and ambulation [8].

High impact information on Gc

• We report here that NGF treatment significantly reduces both the total neuronal and cholinergic neuronal death found 2 weeks after fimbria fornix transection; there was a sparing of 50% of the neurons in the MS and essentially 100% of those in the VDB that otherwise would have died [9].
• In experiments 1-3, excitotoxic lesions were made of the septum and VDB in rats using quisqualic acid, which resulted in significant reductions in ChAT activity in the hippocampus and cingulate cortex, but with no effects on cortical monoamines [4].
• Four experiments examined the role of the cholinergic projections from the septum and vertical limb nucleus of the diagonal band of Broca (VDB) in acquisition and performance of a conditional visual discrimination [4].
• By transient transfection analysis, we identified three regions in the 5'-flanking region of the rat DBP gene, segments F-2, B, and A, that contain tissue-specific transcriptional determinants [10].
• These results suggested that the net expression of the DBP gene reflected a balance between the two major HNF1 species; the relative abundance of HNF1alpha and HNF1beta proteins in a cell may thus play a critical role in determining the pattern of gene expression [10].

Chemical compound and disease context of Gc

• Correlation of these results with glucose, transaminases, and immunoreactive TXB2 and 6-keto-PGF1 alpha indicated that decreased absolute levels of Gc represent a consistent early change in endotoxic shock and that the percentage of Gc complexed is an accurate prognostic indicator of severity [2].

Biological context of Gc

• The different human Gc isoforms have similar NH2-terminal and COOH-terminal amino acid sequences [11].
• By DNA sequence analysis this 1655-base pair clone contains a single open reading frame encoding the 476-amino acid containing full-length DBP and includes its 16-amino acid signal sequence [1].
• Vitamin D binding protein (DBP) is an abundant serum glycoprotein secreted by the liver which transports vitamin D sterols, binds to actin, and is found on the surface of B-lymphocytes and subpopulations of T-lymphocytes [1].
• The serum vitamin D-binding protein (DBP), a member of a multigene family that includes alpha-fetoprotein (alpha FP) and albumin (ALB), is expressed at high levels in the adult liver [12].
• To examine the nature of the DBP mRNA from these nonhepatic sources, a Sprague-Dawley kidney cDNA library was screened, and a single cDNA recombinant was identified [12].

Anatomical context of Gc

• In addition, DBP mRNA was found in the adult kidney, testis, abdominal fat, and 18-day fetal yolk sac [12].
• The tissues in which DBP gene transcripts were noted by Northern analysis were paralleled at 20 cycles of PCR with liver much greater than kidney, yolk sac, testis, and abdominal fat [12].
• Although several studies have demonstrated the presence of DBP on the cell surface of immunocytes and cytotrophoblasts, evidence of extra-hepatic DBP synthesis remains inconclusive [12].
• Nerve growth factor (NGF) acts through trkA receptors to serve as a trophic factor for cholinergic neurones in the medial septal nucleus (MSN) and vertical limb of the diagonal band (VDB) [13].
• We examined the performance of Long-Evans rats with 192 IgG-saporin lesions of the medial septum/vertical limb of the diagonal band (MS/VDB) or nucleus basalis magnocellularis/substantia innominata (NBM/SI), which removed cholinergic projections mainly to hippocampus or neocortex, respectively [14].

Associations of Gc with chemical compounds

• The encoded DBP contains a characteristic placement of cysteine residues, identical to that in albumin, suggesting a similar secondary folding structure [1].
• Cellular Gc was also phosphorylated in intact cells following treatment with carbachol as a physiological stimulus [15].
• Recently, a new extracellular pool of unsaturated fatty acids including arachidonate has been found in relation to group-specific component (Gc), a vitamin D-binding plasma protein that sequesters monomeric G-actin [2].
• Determination of genotypes was performed by coat color and polyacrylamide gel electrophoresis (PAGE of serum protein for the Gc and albumin genes [16].
• We have found that in ethanol-fed rats there was a significant reduction in the total number of Nissl-stained and cholinergic neurons in the MS/VDB, and that the suppression of ethanol intake further decreased neuron numbers [3].

Other interactions of Gc

• Minor changes (+/- 20%) are observed for Gc-globulin, ceruloplasmin, and alpha1-macroglobulin [17].
• Drastic changes in amount of protein were observed at more than 20 spot positions including those of transferrin, Gc-globulin and low-density lipoprotein [18].

Analytical, diagnostic and therapeutic context of Gc

• Using Northern blot analysis of RNA from multiple rat tissues, the DBP transcripts were present in the expected high levels in the adult liver [12].
• Unexpectedly, at 32 cycles of PCR, DBP, alpha FP, and ALB mRNAs could be detected at very low levels in all tissues examined [12].
• This DBP cDNA clone was identified by immunoblotting and its identity was confirmed by immunoprecipitation of a 54-kDa protein after hybrid-assisted translation [1].
• Actin affinity chromatography in the purification of human, avian and other mammalian plasma proteins binding vitamin D and its metabolites (Gc globulins) [19].
• This simple, direct-staining technique appears to be suitable for identifying DBP/Gc phenotypes in human populations as well as for semiquantitatively monitoring the plasma actin-scavenger system in vivo in animal models or in human diseases [20].

References