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1. KCNB1 ‐Leptin receptor complexes couple electric and endocrine function in the melanocortin neurons of the hypothalamus

   https://doi.org/10.1096/fj.202401931R  

   Forzisi‐Kathera‐Ibarra, Elena; Jo, Chanmee; Castillo, Leonard; Gaur, Anika; Lad, Prachi; Bortolami, Alessandro; Roser, Christian; Venkateswaran, Srinidi; Dutto, Stefania; Selby, Matthew; et al (October 2024, The FASEB Journal)

   Abstract The neurons of the melanocortin system regulate feeding and energy homeostasis through a combination of electrical and endocrine mechanisms. However, the molecular basis for this functional heterogeneity is poorly understood. Here, a voltage‐gated potassium (Kv⁺) channel named KCNB1 (alias Kv2.1) forms stable complexes with the leptin receptor (LepR) in a subset of hypothalamic neurons including proopiomelanocortin (POMC) expressing neurons of the Arcuate nucleus (ARH^POMC). Mice lacking functional KCNB1 channels (NULL mice) have less adipose tissue and circulating leptin than WT animals and are insensitive to anorexic stimuli induced by leptin administration. NULL mice produce aberrant amounts of POMC at any developmental stage. Canonical LepR‐STAT3 signaling—which underlies POMC production—is impaired, whereas non‐canonical insulin receptor substrate PI3K/Akt/FOXO1 and ERK signaling are constitutively upregulated in NULL hypothalami. The levels of proto‐oncogene c‐Fos—that provides an indirect measure of neuronal activity—are higher in arcuate NULL neurons compared to WT and most importantly do not increase in the former upon leptin stimulation. Hence, a Kv channel provides a molecular link between neuronal excitability and endocrine function in hypothalamic neurons. 

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2. A basal actinopterygian melanocortin receptor: Molecular and functional characterization of an Mc2r ortholog from the Senegal bichir (Polypterus senegalus)

   https://doi.org/10.1016/j.ygcen.2022.114105  

   Shaughnessy, Ciaran A; Jensen, Mary F; Dores, Robert M (November 2022, General and Comparative Endocrinology)
3. Trends in the evolution of the elasmobranch melanocortin-2 receptor: Insights from structure/function studies on the activation of whale shark Mc2r

   https://doi.org/10.1016/j.ygcen.2023.114278  

   Hoglin, Brianne E; Miner, Marin V; Erdenebayar, Uguumur; Shaughnessy, Ciaran A; Dores, Robert M (July 2023, General and Comparative Endocrinology)
4. Molecular and pharmacological analysis of the melanocortin-2 receptor and its accessory proteins Mrap1 and Mrap2 in a Squalomorph shark, the Pacific spiny dogfish

   https://doi.org/10.1016/j.ygcen.2023.114342  

   Bouyoucos, Ian A; Shaughnessy, Ciarán A; Gary_Anderson, W; Dores, Robert M (October 2023, General and Comparative Endocrinology)
5. Human Melanocortin-2 Receptor: Identifying a Role for Residues in the TM4, EC2, and TM5 Domains in Activation and Trafficking as a Result of Co-Expression with the Accessory Protein, Mrap1 in Chinese Hamster Ovary Cells

   https://doi.org/10.3390/biom12101422  

   Davis, Perry V; Shaughnessy, Ciaran A; Dores, Robert M (October 2022, Biomolecules)

   Human melanocortin-2 receptor (hMC2R) co-expressed with the accessory protein mouse (m)MRAP1 in Chinese Hamster Ovary (CHO) cells has been used as a model system to investigate the activation and trafficking of hMC2R. A previous study had shown that the N-terminal domain of mMRAP1 makes contact with one of the extracellular domains of hMC2R to facilitate activation of hMC2R. A chimeric receptor paradigm was used in which the extracellular domains of hMC2R were replaced with the corresponding domains from Xenopus tropicalis MC1R, a receptor that does not interact with MRAP1, to reveal that EC2 (Extracellular domain 2) is the most likely contact site for hMC2R and mMRAP1 to facilitate activation of the receptor following an ACTH binding event. Prior to activation, mMRAP1 facilitates the trafficking of hMC2R from the ER to the plasma membrane. This process is dependent on the transmembrane domain (TM) of mMRAP1 making contact with one or more TMs of hMC2R. A single alanine substitution paradigm was used to identify residues in TM4 (i.e., I163, M165), EC2 (F167), and TM5 (F178) that play a role in the trafficking of hMC2R to the plasma membrane. These results provide further clarification of the activation mechanism for hMC2R. 

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