Chromogranin A

Chromogranin A is a protein secreted in several environments. While it is primarily released in the adrenal medulla with catecholamines (norepinephrine, epinephrine, dopamine, and others), CgA is often found stored in the granules of endocrine cells in the GI tract. CgA is the precursor molecule for several active molecules. Vasostatin-1 and -2 are involved in regulation of various effects of the cardiovascular system, including blood pressure and stroke volume, by opposing the action of catecholamines. Catestatin decreases release of catecholamines. Pancreastatin decreases insulin secretion. A number of other molecules are also derived from CgA.

Chromogranin A and its derivatives are biomarkers for several conditions. 60-80% of neuroendocrine tumor patients demonstrated elevated chromogranin A. A connection with Alzheimer’s disease has recently been reported. Rheumatoid arthritis and lupus patients may have elevated CgA as a result of increased tumor necrosis factor. Various forms of cancer, kidney disease, and elevated cortisol can also impact chromogranin A level.

Elevated CgA has also been linked to a number of inflammatory GI conditions. 30-50% of IBD patients with active disease have elevated serum CgA. In ulcerative colitis, fecal chromogranins were elevated but not correlated with disease activity. Conflicting results have been seen in patients with Crohn’s disease. Some studies have reported an increased amount of CgA containing cells in patients with IBS.

There are a number of methods for quantifying chromogranin A. Proton pump inhibitors and H2 antihistamines can yield false positive results. A study compared several commercial kits for measuring chromogranin A and found that the radioimmunoassay (RIA) kit was most likely to be accurate with a sensitivity of 93% and specificity of 85%. This means that 93% of the time, this kit properly identified patients with high CgA as having high CgA, while 85% of the time, it properly identified patients with normal CgA as having normal CgA. Currently, there are multiple test methods for quantifying serum and plasma CgA with no central standardization.

Chromogranin A is a constituent of granules in rat mast cells. Tumor necrosis factor is a mediator released by mast cells and may also influence the levels of chromogranin A in mast cell patients. One study found that 31.5% of patients with mast cell activation disease (in a cohort mostly composed of MCAS patients) demonstrated elevation of serum CgA. This same study concluded that plasma heparin and 24 urine testing for prostaglandin D2 and 9a,11b-prostaglandin F2 were the most sensitive markers for mast cell activation with other mediators being less effective.

References:

Gut P, et al. (2016) Chromogranin A – unspecific neuroendocrine marker. Clinical utility and potential diagnostic pitfalls. Arch Med Sci, 12(1): 1-9.

Wernersson S, Pejler G. (2014). Mast cell secretory granules: armed for battle. Nature Reviews Immunology, 14: 478-494.

D’Amico MA, et al. (2014) Biological function and clinical relevance of chromogranin A and derived peptides. Endocrin Connect, 3(2):R45-54.

Mazzawi T, et al. (2015) Increased chromogranin A cell density in large intestine of patients with irritable bowel syndrome after receiving dietary guidance. Gastroenterology Research and Practice, Article ID 823897.

Zenker N, Afrin LB. (2015) Utilities of various mast cell mediators in diagnosis mast cell activation syndrome. Blood, 126:5174.

Massironi S, et al. (2016). Chromogranin A and other enteroendocrine markers in inflammatory bowel disease. Neuropeptides, xxx, xxx-xxx.

How to activate mast cells: Receptors and ligands Master Table (part 1)

There are many receptors on mast cells.  The molecules that bind to these receptors are called ligands.  Different receptors can cause activation in different ways.

I am posting this table a little at a time as I anticipate getting a lot of questions about it.  I put this together for my own reference and I didn’t keep track of all sources.  I am hoping to go through the literature again and track this at some point.

These tables are not exhaustive, and I’ll add to them over time as I have the chance.

Receptor Ligand (molecules that bind to the receptor) Result
0X40 0X40 ligand Suppression of mast cell activation
A2A, A2B, A3 Adenosine At low concentration, degranulation:

histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

De novo: IL-1b, IL-3, IL-4, IL-8, IL-13

 

At high concentration, inhibits FcεRI degranulation

C3α receptor C3α De novo:
IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Increases IgE and IgG dependent degranulation

C5α receptor C5α Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

Cannabinoid CB2 receptor 2-arachidonoyl-glycerol, anandamide Suppression of mast cell activity
CCR1 CCL3 (MIP1α), CCL5 (RANTES) Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
CCR3 CCL11 No degranulation
Increases IgE dependent secretion: IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5
CCR4 CCL2 (MCP-1) No degranulation, reléase of cytokines
CCR5 CCL3 (MIP1α), CCL5 (RANTES), CCL4 (MIP1β) No degranulation, reléase of cytokines
CD200 receptor CD200 (OX2) Inhibitory
Cd300α receptor Eosinophilic granule proteins Inhibitory
CD47 (integrin associated protein, IAP) Integrins Histamine secretion
CD48 E. coli, M. tuberculosis Degranulation : histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

 

De novo : TNFa, IL-6

CD72 CD100 Inhibits CKIT activation
CKIT receptor tyrosine kinase (CD117) Stem cell factor De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

 

Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin

Corticotropin/ corticotropin releasing hormone receptor CRH, urocortin Secretion of VEGF
CX3CL1 Fractalkine No degranulation
CX3CR1 Chemokines No degranulation, reléase of cytokines
Estrogen receptor Estrogens Increased IgE dependent degranulation: histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin
ETA Endothelin-1 Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo: TNFa, IL-6, VEGF, TGF-b1

ETB Endothelin-1 Unknown
FcαR (CD89) IgA Unknown
FcγRIIA, FcγRI, FcγRIIIA IgG/antigen Degranulation: Histamine, tryptase, carboxypeptide, chymase, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5

FcγRIIIB IgG/antigen Cannot induce activation
FcεRI IgE with or without antigen Degranulation: Histamine, tryptase, carboxypeptide, chymas, heparin, chondroitin, renin

 

De novo:
PGD2, leukotriene B4, leukotriene C4, PAF, IL-3, IL-4, IL-5 IL-6, IL-8, IL-10, IL-13, TNF, GM-CSF, CCL2, CCL3, CCL5