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Description

A pituitary hormone secreted from the pars intermedia, MSH was one of the first adenohypophysial hormones demonstrated to be present in vertebrates, from jawless fish to mammals, together with adrenocorticotropic hormone (ACTH). The fact that MSH is derived from a precursor protein called proopiomelanocortin (POMC) was demonstrated in 1979, using the pars intermedia from the bovine pituitary.

Uses

alpha-Melanocyte Stimulating Hormone amide is an endogenous melanocortin receptor agonist (Ki values are 0.12, 31, 660 and 5700 nM for MC1, MC3, MC4 and MC5 receptors respectively). Anti-inflammatory peptide; antagonizes proinflammatory mediators, including TNF-α, IL-6 and NO and induces anti-inflammatory cytokine IL-10. Inhibits food intake and induces penile erections following i.c.v. administration.

General Description

α-Melanocyte-stimulating hormone (α-MSH) is a tridecapeptide, mostly produced by the cells in the brain, pituitary and circulation. Pro-inflammatory cytokines or UV light induced epidermal cells such as keratinocytes and melanocytes synthesize and discharge α–MSH. Poopiomelanocortin (POMC) acts as a precursor for α-Melanocyte-stimulating hormone (α-MSH) production.

Biochem/physiol Actions

α-Melanocyte-stimulating hormone (α-MSH) acts as an anti-inflammatory agent via down regulating the production and activity of the pro-inflammatory cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF)-α and IL-6 expressed in various cells of the immune system. It also controls the nitric oxide production associated with inflammation. α?MSH inhibits nuclear factor-κB (NF-κB)-dependent gene transcription and NF-κB pathway induced by TNF and other inflammatory agents. This activity of α-MSH is mediated through the production of cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA) enzyme. α–MSH functions as a potent therapeutics for various conditions resulted through NF-κB activation including, inflammatory diseases, human immunodeficiency virus (HIV) replication in AIDS (acquired immunodeficiency syndrome), and septic shock. α-MSH has an essential role to play in melanin production in animals. α-MSH regulates development of several skin diseases, including cutaneous inflammation and hyper-proliferative skin diseases.

Clinical Use

The measurement of the blood concentration of MSH has not been validated for routine clinical use. MSH analogs have recently been developed for antiobesity medication, treatment of skin diseases, and prevention of actinic keratoses in organ transplant recipients. The potential use of radiolabeled α-MSH peptides in melanoma imaging and the treatment of disseminated disease has also been reported.

storage

Desiccate at -20°C

Purification Methods

Its solubility in H2O is 1mg/mL. It is separated from the extract by ion-exchange on carboxymethyl cellulose, desalted, evaporated and lyophilised, then chromatographed on Sephadex G-25. [Lande et al. Biochemical Preparations 13 45 1971.]

Structure and conformation

Three types of MSH molecules, with different amino acid sequences, are contained in the common precursor POMC in mammals. α-Melanocyte-stimulating hormone (α-MSH) is composed of 13 aa residues. This peptide is generated from the N-terminal region of the adrenocorticotropic hormone (ACTH), and corresponds to acetylACTH(1–13)-amide. In MSH, the N-terminal Ser residue is free, monoacetylated at the N position, or diacetylated at the N and O positions, whereas the carboxyl terminal is consistently in the amide form. These variations of MSH are called desacetyl-α-MSH, α-MSH, and diacetyl-α-MSH, respectively. Of these peptides, α-MSH is a classical α-MSH. β-MSH, which is generated from POMC via β-lipotropin (β-LPH), is composed of 18 aa residues. Unlike α-MSH, in β-MSH both termini are free. γ-MSH is produced from POMC via pro-γ-MSH or N-POMC, which consists of γ-MSH together with a joining peptide. γ-MSH (also known as γ1-MSH) is composed of 12 aa residues in which the N-terminus and the C-terminus are free and amide, respectively. γ3-MSH is composed of 25 aa residues in which the N-terminal region corresponds to γ1-MSH. Each MSH segment is flanked by basic amino acid residues. Cartilaginous fish such as sharks, rays, and ratfish possess δ-MSH in addition to the three other MSH peptides. Comparison with the amino acid sequence and topology of POMC suggests that δ-MSH might have evolved from β-MSH. Accordingly, α-MSH and γ-MSH are suggested to share an antecedent. Teleost POMC lacks γ-MSH.

Questions And Answer

• Synthesis and release

  In rodents, α-MSH release is under strong inhibitory control by direct innervation from hypothalamic neurons. Dopamine plays a role as a physiological melanotropin release-inhibiting hormone (MRIH). In contrast to ACTH release from corticotropes in the pars distalis of the pituitary, there is no apparent negative feedback control on α-MSH release from melanotropes. Similar mechanisms of regulation have also been demonstrated in amphibians. In humans, the pars intermedia is functional in the fetus and neonate, whereas adults lack the pars intermedia.;

• Receptors

  α-MSH and other MSH peptides interact with four of the five subtypes of melanocortin receptors (MC1R, MC3R, MC4R, and MC5R, excluding the ACTH-specific receptor MC2R), which are members of the GPCR family. Among them, MC1R is a classical α-MSH receptor. ACTH interacts with all five MC receptors. α-MSH activates the AC/PKA pathway via G proteins. ;

• Agonists and Antagonists

  NDP-MSH and MT-II are agonists for human MC1R, MC3R, MC4R, and MC5R. Kd for [¹²⁵I]NDP-MSH: 0.33 nM (MC1R), 0.2 nM (MC3R), 4–1.2 nM (MC4R), 2.8 nM (MC5R). HS024 is an antagonist for human MC1R, MC3R, MC4R, and MC5R.;

• Clinical implications

  The antiinflammatory activity of α-MSH includes immunomodulatory effects on several resident skin cells and antifibrogenic effects mediated via MC1R that are expressed by dermal fibroblasts. In human mast cells, α-MSH appears to be proinflammatory due to histamine release. α-MSH exhibits cytoprotective activity against ultraviolet B-induced apoptosis and DNA damage, which is associated with the increased risk of cutaneous melanoma in individuals with the loss of function MC1R mutation. The congenital deficiency of POMC results in a syndrome of hypoadrenalism, severe obesity, and altered skin and hair pigmentation. In one case from a Turkish family, a child who was homozygous for a frameshift mutation in the N-terminal region of POMC, and was thus predicted to have a loss of all POMC-derived peptides, showed typical symptoms of POMC deficiency. However, this child did not have red hair, unlike cases of Northern European origin.;

• Biological functions

  α-MSH and other MSH peptides are associated with a wide spectrum of biological functions through MC receptors that distribute in many tissues. MC1R is expressed in melanocytes, keratinocytes, macrophages, leukocytes, and adipose tissue; MC3R is expressed in the central nervous system (CNS), kidney, testis, ovary, skeletal muscle, placenta, and mammary gland; MC4R is expressed in the CNS and associated with food intake; and MC5R is expressed in exocrine glands, muscle, and the CNS. The representative physiological functions of MSH peptides mediated by MC receptors are stimulation of melanocytes in the skin to synthesize melanin, including regulation of the eumelaninpheomelanin switch via MC1R; energy homeostasis and natriuresis via MC3R; energy homeostasis and erectile function via MC4R; and synthesis and secretion of exocrine gland products via MC5R.;

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