Disease relevance of CALCA

• These preliminary data suggest a strong positive association of the CALCA C allele with the risk of ovarian cancer among some subgroups [1].
• Hypermethylation of CpG island in the promoter region of CALCA in acute lymphoblastic leukemia with central nervous system (CNS) infiltration correlates with poorer prognosis [2].
• In particular, CGRP has potent activity in the cerebral circulation, which is possibly relevant to the pathology of migraine, whilst vascular sources of AM contribute to dysfunction in cardiovascular disease [3].
• CT derives from the C cells of the thyroid gland and is the most potent peptide inhibitor of osteoclast-mediated bone resorption [4].
• Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) are potent dilators of human brain arteries, and they have been implicated in the neurogenic inflammation underlying migraine headache and in the evolution of stroke, respectively [5].

Psychiatry related information on CALCA

• Ethanol-induced release of CGRP may contribute to the reduction in the risk of CAD associated with alcohol consumption by various mechanisms, including the increase in coronary flow and arterial dilatation [6].
• Thus, it is thought that both CT and A beta, which are formed during the processing of APP, may participate in the neuronal degeneration in Alzheimer's disease by different mechanisms [7].
• Thus upregulation of CGRP mRNA and iCGRP levels are temporally related to the development of inflammation and lowered pain thresholds [8].
• In a rat model of tendon rupture using semiquantitative methodology, healing was assessed according to the diameter of newly organized collagen and the occurrence of the sensory neuropeptides (SP, CGRP) in relation to different levels of physical activity [9].
• Conversely, in the hot-plate test CGRP was effective in enhancing response latencies only at the highest dose of 10 micrograms/rat, while sCT (0.125, 0.25 and 2.5 micrograms/rat) inhibited the hot-plate response dose-dependently [10].

High impact information on CALCA

• This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM) [3].
• Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented [3].
• CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas [3].
• The calcitonin/CGRP gene is a complex transcription unit in which developmentally regulated cell-specific alternative RNA processing results in the production of CGRP mRNA in neurons, and of calcitonin mRNA in thyroid C cells [11].
• Splice commitment dictates neuron-specific alternative RNA processing in calcitonin/CGRP gene expression [11].

Chemical compound and disease context of CALCA

• Since it has recently been shown that human CGRP (hCGRP) lowers plasma calcium levels in both the rat and the rabbit, we examined the in vitro effects of human synthetic CGRP on bone resorption (as measured by 45Ca release) stimulated by PTH, prostaglandin E2, and 1,25-dihydroxyvitamin D3 [12].
• CGRP (10(-6)-10(-8) M) also inhibited resorption stimulated by prostaglandin and 1,25-dihydroxyvitamin D3 in a dose-dependent manner, but had no significant effect on basal bone resorption [12].
• Structure-activity relationships for the binding of human alpha-calcitonin gene-related peptide 8-37 (halphaCGRP8-37) have been investigated at the CGRP receptors expressed by human SK-N-MC (neuroblastoma) and Col 29 (colonic epithelia) cells by radioligand binding assays and functional assays (halphaCGRP stimulation of adenylate cyclase) [13].
• We conclude that WE-68 Ewing's sarcoma cells express genuine CGRP receptors which upon activation lead to stimulation of cyclic AMP formation[14]
• In Xenopus oocytes with an endogenous calcitonin gene-related peptide (CGRP) receptor, a receptor activity modifying protein (RAMP1) enhancing CGRP stimulated chloride currents of the cystic fibrosis transmembrane regulator was recently cloned [McLatchie, L.M. et al. (1998) Nature 393, 333-339] [15].

Biological context of CALCA

• This chromosome segment includes the genes for insulin-like growth factor 2, beta-hemoglobin, calcitonin A (CALCA), and parathyroid hormone (PTH) [16].
• Women with any CALCA C allele were at nonsignificantly higher risk of ovarian cancer (OR: 1.5, 95% CI: 0.9-2.3) compared to women with the TT genotype and the risk increased with the number of C alleles (P for trend: 0.05) [1].
• Data from a population-based case-control study conducted in Hawaii were used to examine the hypothesis that a T --> C transition 624 base pairs upstream (-624) of the translation initiation codon of the CALCA gene influences the risk of ovarian malignancy [1].
• Considering the patients with central nervous system (CNS) infiltration, the estimated 2-year overall survival (OS) was 20% for those with methylation in CALCA promoter and 85% for those without (p=0.001) [2].
• These results suggest that mitotic deletion mapping may be as useful as meiotic deletion or recombination mapping in ordering closely linked markers, such as CALCA and PTH, for which other approaches, including physical mapping and multipoint linkage analysis, have failed to accurately identify the gene order [17].

Anatomical context of CALCA

• DNA extracts from normal leukocytes and 48 tumor samples were analyzed by Southern blotting using the polymorphic probes pEJ6.6 (HRAS1), phins310 (INS), p20.36 (PTH), and pEM36 (CALCA) [18].
• We now report that human pancreatic amylin and rat CGRP-1 are potent inhibitors of both basal and insulin-stimulated rates of glycogen synthesis in stripped rat soleus muscle in vitro [19].
• Transfection of this cDNA into COS cells resulted in expression of receptors with high affinity for salmon CT (Kd = approximately 0.44 nM) and for human CT (Kd = approximately 5.4 nM) [20].
• In conclusion, CGRP II, unlike CGRP I, inhibits gastric acid secretion in humans [21].
• The amino acid sequence of CGRP-I was obtained in medullary thyroid carcinoma extracts (Morris, H. R., Panico, M., Etienne, T., Tippins, J., Girgis, S. I., and MacIntyre, I. (1984) Nature 308, 746-748), but not in normal human tissues [22].

Associations of CALCA with chemical compounds

• Furthermore, step-doses of CGRP I and CGRP II (79-320 pmol/kg.h) were given intravenously on continuous pentagastrin stimulation and compared with calcitonin (88-352 pmol/kg.h) [21].
• The loop has been analyzed by systematic mutagenesis of all residues to alanine, measuring cAMP accumulation, CGRP affinity, and receptor expression [23].
• Also this effect of ADM occurs via CGRP1 receptors, which are coupled with the adenylate cyclase-dependent cascade [24].
• ADM directly supresses angiotensin-II- and K+-stimulated aldosterone secretion from ZG cells, acting through calcitonin gene-related peptide (CGRP) type 1 ADM(22-52)-sensitive receptors, the activation of which is likely to impair Ca2+ influx [24].
• ADM exerts a mitogenic effect on rat ZG, acting via CGRP1 receptors that activate the tyrosine kinase-dependent mitogen-activated protein kinase cascade [24].
• Elevated calcitonin gene-related peptide, but not substance P or neurokinin A, is only associated with chronic cough in children when oesophagitis coexists [25].

Physical interactions of CALCA

• CGRP binding and receptor activation lead to the phosphorylation of CRLR and the internalization of the receptor as a stable complex [26].
• The anatomical distribution and the pharmacological characteristics of amylin binding sites in the rat brain are different from those reported for CGRP but share several similarities with the salmon calcitonin receptors [27].
• Coupling of hADM binding to cAMP stimulation is less efficient than for hCGRP-I and is reduced by deletion of the unique 12 amino acid sequence of hADM N-terminal to the ring structure [28].
• Because neutrophil infiltration of the clear corneal surface is a hallmark of corneal inflammation in the human eye, we determined whether CGRP can bind to human corneal epithelial cells (HCEC) and induce expression of the neutrophil chemotactic protein IL-8 [29].
• These studies suggest that CGRP initially interacts with the calcitonin receptor to produce a calcitonin-like effect, which is followed by hypercalcaemia presumably by antagonising the action of endogenous circulating calcitonin [30].

Regulatory relationships of CALCA

• The binding of CGRP and its ability to stimulate cAMP production were investigated in mutant and wild-type receptors after transient transfection into COS-7 cells with RAMP1 [31].
• Furthermore, CGRP-induced relaxation of placental vessels are inhibited by a CGRP receptor antagonist (CGRP8-37), ATP-sensitive potassium (KATP) channel blocker (glybenclamide), and cAMP-dependent protein kinase A inhibitor (Rp-cAMPS) and partially inhibited by a nitric oxide inhibitor (Nomega-nitro-l-arginine methyl ester) [32].
• We found that CGRP-expressing fibers in the pancreatic islets also express TRPV1 [33].
• In conclusion, both CGRP and adrenomedullin induced vasodilation via CGRP receptors in human lenticulostriate artery of various diameter [34].
• We conclude that, in addition to the previously characterized direct smooth muscle relaxant action via CGRP1 receptors (Maggi et al. Regulatory Peptides 61, 27-36, 1996), CGRP also induces a remarkable potentiation of excitatory neurotransmission to the circular muscle of the guinea-pig colon via CGRP2 receptors [35].

Other interactions of CALCA

• Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP [36].
• A non-BWS translocation breakpoint was more proximal, between HBB and calcitonin-A (CALCA) [37].
• In addition, human alpha-CGRP (8-37) is an effective antagonist of the hemodynamic actions of rat IAPP [38].
• Interestingly, the L94A mutant up-regulated surface expression of the receptor heterodimer to a greater degree than wild-type hRAMP1, thereby increasing CGRP binding and signaling [39].
• Our data suggest that the neuroendocrine peptides VIP, CGRP, and CT may exert functional roles during MG and malignant transformation of the human thymus [40].

Analytical, diagnostic and therapeutic context of CALCA

• The present study was undertaken to compare in healthy volunteers the effects of intravenous infusions of CGRP I and CGRP II (79 pmol/kg.h) on pentagastrin-stimulated acid secretion to those of calcitonin (88 pmol/kg.h) [21].
• CGRP expression was confirmed in cultured decidual cells by Southern blot analysis and immunocytochemistry and by RIA in culture medium [41].
• After total thyroidectomy, the samples were examined for CT, chromogranin A, and SSTR expression by RT-PCR [42].
• The CGRP dose-dependently increased (up to 50-fold) cAMP formation in cell cultures, an effect significantly blocked by 0.1 to 10 micromol/L of the CGRP1 receptor antagonist CGRP8-37 [5].
• 3. In experiments measuring changes in local blood flow in rat skin by a 133xenon clearance technique, intradermal injection of both ADM13-52 (3-300 pmol) and CGRP (0.1-30 pmol) evoked dose-related increases in local blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)[43]

References