Arginine Residue 155 in the Second Intracellular Loop Plays a Critical Role in Rat Melanin-Concentrating Hormone Receptor 1 Activation

Saito, Yumiko; Tetsuka, Mitsue; Saito, Seiji; Imai, Kanae; Yoshikawa, A.; Doi, Hirofumi; Maruyama, Kei

doi:10.1210/en.2005-0115

Cited by 29 publications

(25 citation statements)

References 47 publications

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“…Furthermore, Arg14 of MCH peptide is an important residue to interact with Asp123 site of MCH1R. Arg155 in intracellular loop 2 of MCH1R has been shown to play a critical role in receptor function since Arg155 mutation led to a drastic loss of MCH1R signal transduction without changing the high affinity constant (Kd) value [34]. Also, a point mutation in Thr255 which is located at the junction of intracellular loop 3 and transmembrane domain 6 resulted in the receptor being retained in the endoplasmic reticulum; it dramatically reduced the MCH1R cell surface expression level.…”

Section: Pharmacological Characteristics Of the Mch Receptormentioning

confidence: 99%

MCH receptors/gene structure-in vivo expression

Chung¹,

Saito²,

Civelli³

2009

Peptides

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Melanin-concentrating hormone (MCH) is a cyclic peptide which was originally discovered in fish to lighten skin color by affecting melanosomes aggregation. This peptide is highly conserved and also found in rodents whose gene is overexpressed upon fasting. However, the site of MCH action remained obscure until its receptor was discovered in 1999 as a G protein-coupled receptor. After this receptor structure was identified, the functional domains important for MCH-MCHR interaction were revealed. Moreover, the cloning of the MCH receptor led us to identify the in vivo sites of MCH action which suggested potential physiological functions of the MCH system. Furthermore, the MCH receptor identification allow for designing surrogate molecules which can block MCH activity. Studies using these molecules revealed various physiological functions of the MCH system not only in feeding but also in other physiological responses such as stress and emotion. This review will discuss how the MCH receptor was discovered and its impact on many studies investigating the MCH receptor’s structure, signaling pathways, and expression pattern.

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Section: Pharmacological Characteristics Of the Mch Receptormentioning

confidence: 99%

MCH receptors/gene structure-in vivo expression

Chung¹,

Saito²,

Civelli³

2009

Peptides

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“…Importantly, we identified the C-terminal five amino acids of G␣ q were involved in the interaction with IL2 of receptors. Previous reports showed that multiple substitution of the basic amino acids are required to abolish the receptor function (34,36); however, replacement of Arg-164 alone in PKR2 with amino acids other than positive-charged ones was able to disrupt the receptor function. Nevertheless, studies on the closely related PKR1 indicated that the equivalent Arg-173 does function cooperatively with surrounding basic amino acids.…”

Section: Discussionmentioning

confidence: 97%

“…Mutation in this region can selectively abolish the G␣ q -coupling of PTH/PTH-related protein receptor but retain the G␣ s -coupling capacity (35). However, Saito et al demonstrated a basic amino acid (Arg-155) in the IL2 of MCHR1 plays a critical role in the G-protein coupling and activation but not selectivity, as both G␣ q and G␣ i -coupled pathway are disrupted by R155Q mutation (36).…”

Section: Discussionmentioning

confidence: 99%

Disease-causing Mutation in PKR2 Receptor Reveals a Critical Role of Positive Charges in the Second Intracellular Loop for G-protein Coupling and Receptor Trafficking

Peng

Tang

Luo

et al. 2011

Journal of Biological Chemistry

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Prokineticins are a pair of signal factors involved in many physiological processes by binding to two closely related G-protein-coupled receptors, PKR1 and PKR2. Recently, mutations in prokineticin 2 (PK2) and PKR2 are found to be associated with Kallmann syndrome and/or idiopathic hypogonadotropic hypogonadism, disorders characterized by delayed puberty and infertility. However, little is known how PKRs interact and activate G-proteins to elicit signal transduction. In the present study, we took advantage of one disease-associated mutation (R164Q) located in the second intracellular (IL2) loop of PKR2, to investigate the role of IL2 loop in the cell signaling, G-protein binding and receptor trafficking. R164Q mutant PKR2 showed normal cell surface expression and ligand binding capacity. However, the PKR2 signaling was abolished by R164Q mutation. We demonstrated that R164Q mutation disrupted the interaction of IL2 loop to the G␣ q , G␣ i , and G␣ 16 -proteins. A positive-charged amino acid at this position is required for proper function, and the signaling efficacy and potency depend on the net amount of positive charges. We also demonstrated that the interactive partner of Arg-164 may localize in the C-terminal five residues of G␣ q -protein. A series of mutation analysis indicated that the basic amino acids at the C terminus of IL2 loop may function cooperatively in GPCRs. Furthermore, R164Q mutation also results in minimal ligand-induced endocytosis of PKR2. As many GPCRs share structural homology in the C terminus of IL2 loop, our findings may have general application in understanding structure and function of GPCRs. G-protein-coupled receptors (GPCRs)2 are the largest family of membrane-spanning proteins that transduce numerous extracellular signals including light, odorants, hormones, neurotransmitters, and chemokines to the interior of cells and play fundamental roles in regulation of cellular functions. The structure of GPCRs consists of seven transmembrane (TM) helices, with three intracellular loops (IL1-3) and the cytoplasmic C-terminal tail. The extracellular ligands activate GPCRs and enable the receptors to interact with and activate distinct sets of heterotrimeric G proteins (e.g. G␣␤␥) (1).Prokineticins are a pair of signal factors involved in a variety of physiological processes, including gastrointestinal mobility, circadian rhythms, emotion, nociception, angiogenesis, and neurogenesis (2-5). Prokinticins execute their functions by binding to two closely related GPCRs, PKR1 and PKR2 (6, 7). It has been shown that activation of prokineticin receptors (PKRs) leads to accumulation of inositol phosphate and mobilization of intracellular Ca 2ϩ via G␣ q/11 proteins (6). In addition, PKRs may inhibit cAMP accumulation, presumably through G␣ i/o proteins (8). Furthermore, PKRs have been shown to stimulate mitogen-activated protein kinase via G␣ o protein-mediated signaling (6). However, little is known about the structure-function relationships in PKRs, and more extensive research is necessary to iden...

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“…In addition, four epitope domains (amino acids 51-80, 85-98, 154-158, 254-260) have been identified as the antibody binding sites (10). Also, the equivalent peptide sequence to epitopes 51-80 and 85-98, 154-158 and 254-260 in rat McHR1 are predicted to lie in the extracellular N-terminal domain, the first extracellular loop, and the second extracellular loop of the receptor, respectively (19).…”

Section: Discussionmentioning

confidence: 99%