Melanotan Peptides:
MC1R Agonism & Photoprotection
Explore the melanocortin system and its role in pigmentation biology. From α-MSH analogs to receptor pharmacology, understand the science behind melanogenesis research.
Understanding the Melanocortin System
The melanocortin system is a neuroendocrine signaling network that regulates diverse physiological processes including pigmentation, energy homeostasis, sexual function, and inflammation. At its core are five G protein-coupled receptors (MC1R through MC5R) and their endogenous ligands derived from proopiomelanocortin (POMC).
Alpha-melanocyte stimulating hormone (α-MSH) is the primary endogenous ligand for MC1R, the receptor predominantly expressed on melanocytes. When α-MSH binds MC1R, it triggers a signaling cascade that ultimately increases melanin synthesis—the biological process known as melanogenesis.
Melanotan peptides are synthetic analogs of α-MSH designed for enhanced potency, receptor selectivity, and metabolic stability. They serve as valuable research tools for studying melanocortin receptor pharmacology, pigmentation biology, and the broader implications of this signaling system.
5
MC Receptors
POMC
Precursor Gene
cAMP
Second Messenger
Melanogenesis Signaling Pathway
α-MSH / Melanotan
Ligand
MC1R
Melanocyte Receptor
↑ cAMP → PKA → CREB
Second Messenger Cascade
MITF Activation
Master Transcription Factor
Tyrosinase ↑ → Melanin
Pigment Synthesis
MC1R activation drives eumelanin synthesis via the cAMP/MITF pathway.
Peptide Variants
Melanotan I vs. Melanotan II
Two distinct α-MSH analogs with different receptor selectivity profiles and research applications.
Melanotan I (Afamelanotide)
Melanotan I is a linear 13-amino acid peptide ([Nle4, D-Phe7]-α-MSH) with high selectivity for the MC1R receptor. Developed at the University of Arizona, it demonstrates enhanced metabolic stability compared to native α-MSH due to strategic amino acid substitutions that resist enzymatic degradation.
Research Focus: Pigmentation biology, photoprotection studies, melanocyte function assays, erythropoietic protoporphyria models.
Melanotan II
Melanotan II is a cyclic 7-amino acid lactam peptide (Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH2) with broader melanocortin receptor affinity. The cyclic structure provides enhanced stability and allows it to bind multiple receptor subtypes including MC1R, MC3R, MC4R, and MC5R.
Research Focus: Multi-receptor pharmacology, energy homeostasis (MC4R), sexual function studies, appetite regulation models.
The Melanocortin Receptor Family
Five GPCRs with distinct tissue distributions and physiological functions.
Melanocyte Receptor
Skin melanocytes. Primary target for pigmentation. Regulates eumelanin vs. pheomelanin balance.
ACTH Receptor
Adrenal cortex. Binds ACTH exclusively. Controls cortisol synthesis. Not activated by α-MSH.
Metabolic Receptor
Hypothalamus, gut. Involved in energy homeostasis and nutrient partitioning. Modulates feeding behavior.
Satiety Receptor
Hypothalamus, brainstem. Critical for appetite suppression. Also involved in sexual function and blood pressure.
Exocrine Receptor
Sebaceous glands, sweat glands. Regulates sebum production. Role in immune modulation.
Melanogenesis: From Receptor to Pigment
A detailed look at the molecular cascade triggered by MC1R activation.
Step 1: Receptor Activation & cAMP Generation
When α-MSH or Melanotan binds to MC1R, the receptor undergoes a conformational change that activates the stimulatory G protein (Gαs). Gαs activates adenylyl cyclase, which converts ATP to cyclic AMP (cAMP). Elevated intracellular cAMP is the primary second messenger that initiates the melanogenic cascade. The magnitude and duration of cAMP elevation correlates with the degree of pigmentation response.
Step 2: PKA Activation & CREB Phosphorylation
cAMP binds to the regulatory subunits of Protein Kinase A (PKA), releasing the active catalytic subunits. Activated PKA translocates to the nucleus where it phosphorylates CREB (cAMP Response Element Binding protein) at Serine 133. Phospho-CREB then binds to CRE sequences in the promoters of target genes, recruiting transcriptional coactivators like CBP/p300.
Step 3: MITF Upregulation
The critical transcriptional target of CREB in melanocytes is MITF (Microphthalmia-associated Transcription Factor). MITF is the master regulator of melanocyte development and function. CREB binding to the MITF promoter dramatically increases MITF expression. Additionally, PKA can directly phosphorylate MITF, enhancing its transcriptional activity and stability.
Step 4: Melanin Synthesis Enzymes
MITF directly activates transcription of the melanogenic enzyme genes: Tyrosinase (TYR), Tyrosinase-related protein 1 (TYRP1), and Dopachrome tautomerase (DCT/TYRP2). Tyrosinase is the rate-limiting enzyme that catalyzes the initial steps of melanin synthesis—converting tyrosine to DOPA and DOPA to dopaquinone. The pathway then branches toward either brown/black eumelanin or red/yellow pheomelanin.
Scientific Reference
Background on melanocortin signaling and pigmentation biology.
Research Applications
Melanotan peptides serve as tools across multiple research domains.
Photoprotection Studies
Investigating whether increased eumelanin provides photoprotection against UV-induced DNA damage. Research into erythropoietic protoporphyria (EPP) and other photosensitivity disorders.
Melanocyte Biology
Studying melanocyte differentiation, proliferation, and dendricity. Understanding melanosome biogenesis and transfer to keratinocytes. Investigating MC1R signaling dynamics.
MC1R Polymorphism Research
Studying how MC1R variants affect receptor function, pigmentation phenotypes, and UV sensitivity. Understanding the genetics of red hair and fair skin phototypes.
MC4R Pharmacology
Using MT-II to study hypothalamic MC4R signaling in appetite regulation, energy expenditure, and sexual behavior. Investigating MC4R as a therapeutic target for obesity.
Anti-Inflammatory Effects
Melanocortins demonstrate anti-inflammatory properties beyond pigmentation. Research into modulation of cytokine release, NF-κB signaling, and immune cell function.
Receptor Selectivity Studies
Comparing MT-I (MC1R selective) vs. MT-II (non-selective) to dissect individual receptor contributions to physiological responses. Developing more selective analogs.
Melanotan Research Glossary
Key terminology for melanocortin and pigmentation research.
Eumelanin
The brown/black form of melanin that provides photoprotection. High eumelanin correlates with darker skin, hair, and eye color. Produced via the DHI/DHICA pathway.
Pheomelanin
The red/yellow form of melanin. Associated with red hair and fair skin. Synthesized when cysteine or glutathione conjugates with dopaquinone. Less photoprotective than eumelanin.
Melanosome
Specialized organelle within melanocytes where melanin synthesis occurs. Melanosomes are transferred to keratinocytes via dendritic processes to distribute pigment.
MITF
Microphthalmia-associated Transcription Factor. Master regulator of melanocyte development and melanogenic gene expression. Target of the cAMP/PKA/CREB cascade.
POMC
Proopiomelanocortin. Precursor polypeptide cleaved to produce α-MSH, ACTH, β-endorphin, and other peptides. Expression in pituitary, hypothalamus, and skin.
Tyrosinase
Rate-limiting enzyme in melanin synthesis. Copper-containing oxidase that converts L-tyrosine to DOPA and DOPA to dopaquinone. Primary target of MITF transcriptional activation.
Frequently Asked Questions
What is the difference between Melanotan I and Melanotan II?
How does MC1R activation lead to pigmentation?
What role do MC1R polymorphisms play in skin phototype?
Why is MT-II used for sexual function research?
How should Melanotan peptides be stored?
Explore Melanotan Research Peptides
Access high-purity Melanotan I and Melanotan II for melanocortin receptor pharmacology, pigmentation biology, and photoprotection research.
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