Adrenomedullin
Encyclopedia
Adrenomedullin is a peptide
associated with pheochromocytoma
- a tumour arising from adrenal medulla. It was discovered in 1993.
Adrenomedullin (AM) is a ubiquitously expressed peptide initially isolated from phaechromyctoma in 1993 (Kitamura et al., 1998). Since its first report, studies examining the effects of adrenomedullin have mushroomed, highlighting its role in a number of diseases. Recently a second peptide AM2 has been recognised, exhibiting similar functions (Fujisawa et al., 2004).
) and receptor activity-modifying proteins (RAMP2
) complexes, as well as CGRP receptors. It is worth noting that unlike the classical one ligand-one receptor notion of receptor signalling, the interaction of both Calcitonin receptor-like (CALCRL
) and RAMP ( Receptor activity-modifying protein
) at the membrane, is required for AM to mediate its action. The outcome of AM stimulation of its receptor is the cellular production of both cyclic AMP (cAMP) and nitric oxide production. Some may find the production of these inside the cell to be at odds, since often they have opposing effects, but as yet, the timing of these effects remains to be studied.
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
associated with pheochromocytoma
Pheochromocytoma
A pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
- a tumour arising from adrenal medulla. It was discovered in 1993.
Adrenomedullin (AM) is a ubiquitously expressed peptide initially isolated from phaechromyctoma in 1993 (Kitamura et al., 1998). Since its first report, studies examining the effects of adrenomedullin have mushroomed, highlighting its role in a number of diseases. Recently a second peptide AM2 has been recognised, exhibiting similar functions (Fujisawa et al., 2004).
The Adrenomedullin Peptide
The human AM gene is localized to a single locus on Chromosome 11 with 4 exons and 3 introns. The AM gene initially codes for a 185-amino acid precursor peptide [3], that can be differentially excised to form a number of peptides, including an inactive 53-amino acid AM, e PAMP, adrenotensin and AM95-146. Mature human AM is activated to form a 52 amino acid, 6-amino acid ring, that shares moderate structural similarity to the calcitonin family of regulatory peptides (calcitonin, CGRP and amylin). Circulating AM consists of both amidated (mature) and the glycated form (inactive, with the latter comprising the major form (85%) [5]. The measured to have a plasma half-life of 22min, mean clearance rate of 274 mL/kg/min, and apparent volume of distribution of 880+/- 150 mL/kg (Meeran et al., 1997). Mature AM is metabolised via aminopeptidase action.Receptors of Adrenomedullin
At present AM is believed to function through combinations of the calcitonin receptor like receptor (CALCRLCALCRL
Calcitonin receptor-like , also known as the calcitonin receptor-like receptor , is a human protein.- Function :The protein encoded by the CALCRL gene is a G protein-coupled receptor related to the calcitonin receptor...
) and receptor activity-modifying proteins (RAMP2
RAMP2
Receptor activity modifying protein 2, also known as RAMP2, is a protein which in humans is encoded by the RAMP2 gene.- Function :...
) complexes, as well as CGRP receptors. It is worth noting that unlike the classical one ligand-one receptor notion of receptor signalling, the interaction of both Calcitonin receptor-like (CALCRL
CALCRL
Calcitonin receptor-like , also known as the calcitonin receptor-like receptor , is a human protein.- Function :The protein encoded by the CALCRL gene is a G protein-coupled receptor related to the calcitonin receptor...
) and RAMP ( Receptor activity-modifying protein
Receptor activity-modifying protein
Receptor activity-modifying proteins are a class of protein which interact with and modulate the activities of several Class B G Protein-Coupled Receptors including the receptors for secretin, calcitonin , glucagon, and vasoactive intestinal peptide...
) at the membrane, is required for AM to mediate its action. The outcome of AM stimulation of its receptor is the cellular production of both cyclic AMP (cAMP) and nitric oxide production. Some may find the production of these inside the cell to be at odds, since often they have opposing effects, but as yet, the timing of these effects remains to be studied.
The physiological functions of Adrenomedullin
AM was initially identified as a vasodilator, some have cited this as the most potent endogenous vasodilatory peptide found in the body (Cockcroft et al., 1997). Differences in opinion regarding the ability of AM to relax vascular tone arises from the differences in the model system used (Hamid and Baxter, 2005). Other effects of AM include increasing the tolerance of cells to oxidative stress and hypoxic injury and angiogenesis. AM is seen as a positive influence in diseases such as hypertension, myocardial infarction, chronic obstructive pulmonary disease and other cardiovascular diseases, whereas it can be seen as a negative factor in potentiating the potential of cancerous cells to extend their blood supply and cause cell proliferation.Further reading
- Cao et al., Regulated Peptide, 113(1-3),109-114. 2003.
- Cockcroft et al., Br J Clin Pharmacol. 1997 Jul;44(1):57-60.
- Fujisawa Y et al., Eur J Pharmacol. Aug 16;497(1):75-80. 2004.
- Hamid SA, Baxter GF, Pharmacol Ther. Feb;105(2):95-112.2005.
- Kitamura et al., Biochem Biophys Res Commum, 244(2), 551-555. 1998.
- Meeran K et al., J Clin Endocrinol Metab. Jan;82(1):95-100. 1997