Cutaneous pharmacologic cAMP induction induces melanization of the skin and improves recovery from ultraviolet injury in melanocortin 1 receptor‐intact or heterozygous skin

Abstract Background 64Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1–4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone. Results We found that the presence of pyridyl groups significantly increases 64Cu labeling conversion yield, with DOTA-2Py, −3Py and -4Py quantitatively complexing 64Cu at room temperature within 5 min (1 × 10− 4 M). [64Cu]Cu-DOTA-xPy (x = 2–4) exhibited good stability in human serum up to 24 h. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three 64Cu complexes. DOTA-xPy (x = 1–3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [64Cu]Cu-DOTA-xPy-αMSH retained good serum stability (> 96% in 24 h) and showed high binding affinity (Ki = 2.1–3.7 nM) towards the melanocortin 1 receptor. Conclusion DOTA-xPy (x = 1–3) are promising chelators for 64Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.

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Cellular concentrations of protein kinase A modulate prostaglandin and cAMP induction of alkaline phosphatase.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)42493-3 ◽

1992 ◽

Vol 267 (12) ◽

pp. 8658-8665

Author(s):

M.D. Uhler ◽

A Abou-Chebl

Keyword(s):

Alkaline Phosphatase ◽

Protein Kinase ◽

Protein Kinase A ◽

Camp Induction ◽

Kinase A

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High Polymorphism at the Human Melanocortin 1 Receptor Locus

Genetics ◽

10.1093/genetics/151.4.1547 ◽

1999 ◽

Vol 151 (4) ◽

pp. 1547-1557 ◽

Cited By ~ 4

Author(s):

Brinda K Rana ◽

David Hewett-Emmett ◽

Li Jin ◽

Benny H-J Chang ◽

Naymkhishing Sambuughin ◽

...

Keyword(s):

Protein Sequence ◽

Nucleotide Diversity ◽

Coat Color ◽

Low Frequency ◽

Melanocortin Receptor ◽

Human Populations ◽

Melanocortin 1 Receptor ◽

Mc1r Gene ◽

Southeast Asians ◽

Color Changes

Abstract Variation in human skin/hair pigmentation is due to varied amounts of eumelanin (brown/black melanins) and phaeomelanin (red/yellow melanins) produced by the melanocytes. The melanocortin 1 receptor (MC1R) is a regulator of eu- and phaeomelanin production in the melanocytes, and MC1R mutations causing coat color changes are known in many mammals. We have sequenced the MC1R gene in 121 individuals sampled from world populations with an emphasis on Asian populations. We found variation at five nonsynonymous sites (resulting in the variants Arg67Gln, Asp84Glu, Val92Met, Arg151Cys, and Arg163Gln), but at only one synonymous site (A942G). Interestingly, the human consensus protein sequence is observed in all 25 African individuals studied, but at lower frequencies in the other populations examined, especially in East and Southeast Asians. The Arg163Gln variant is absent in the Africans studied, almost absent in Europeans, and at a low frequency (7%) in Indians, but is at an exceptionally high frequency (70%) in East and Southeast Asians. The MC1R gene in common and pygmy chimpanzees, gorilla, orangutan, and baboon was sequenced to study the evolution of MC1R. The ancestral human MC1R sequence is identical to the human consensus protein sequence, while MC1R varies considerably among higher primates. A comparison of the rates of substitution in genes in the melanocortin receptor family indicates that MC1R has evolved the fastest. In addition, the nucleotide diversity at the MC1R locus is shown to be several times higher than the average nucleotide diversity in human populations, possibly due to diversifying selection.

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