Sensitivity of opioid receptor binding to N-substituted maleimides and methanethiosulfonate derivatives

Shahrestanifar, Mandana; Howells, Richard D.

doi:10.1007/bf02532370

Cited by 15 publications

(8 citation statements)

References 23 publications

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“…4). This relationship is consistent with a "chain length effect" that has been found in the inactivation of certain enzymes and receptors (38). A long and flexible side chain (Met, Lys, or Leu) generally facilitated the functional response to external Na ϩ , whereas a shorter side chain (Val, Ala, Thr, Asp, Cys, or Ser) hindered the functional response.…”

Section: Discussionsupporting

confidence: 86%

Novel Determinants of Epithelial Sodium Channel Gating within Extracellular Thumb Domains

Maarouf

Sheng

Chen

et al. 2009

Journal of Biological Chemistry

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Activity of the epithelial Na؉ channel (ENaC) is modulated by Na ؉ self-inhibition, an allosteric down-regulation of channel open probability by extracellular Na ؉ . We searched for determinants of Na ؉ self-inhibition by analyzing changes in this inhibitory response resulting from specific mutations within the extracellular domains of mouse ENaC subunits. Mutations at ␥Met 438 altered the Na ؉ self-inhibition response in a substitution-specific manner. Fourteen substitutions (Ala, Arg, Asp, Cys, Gln, Glu, His, Ile, Phe, Pro, Ser, Thr, Tyr, and Val) significantly suppressed Na ؉ self-inhibition, whereas three mutations (Asn, Gly, and Leu) moderately enhanced the inhibition. Met to Lys mutation did not alter Na ؉ self-inhibition. Mutations at the homologous site in the ␣ subunit (G481A, G481C, and G481M) dramatically increased the magnitude and speed of Na ؉ self-inhibition. Mutations at the homologous ␤Ala 422 resulted in minimal or no change in Na ؉ self-inhibition. Low, high, and intermediate open probabilities were observed in oocytes expressing ␣G481M␤␥, ␣␤␥M438V, and ␣G481M/ ␤␥M438V, respectively. This pair of residues map to the ␣5 helix in the extracellular thumb domain in the chicken acid sensing ion channel 1 structure. Both residues likely reside near the channel surface because both ␣G481C␤␥ and ␣␤␥M438C channels were inhibited by an externally applied and membrane-impermeant sulfhydryl reagent. Our results demonstrate that ␣Gly 481 and ␥Met 438 are functional determinants of Na ؉ self-inhibition and of ENaC gating and suggest that the thumb domain contributes to the channel gating machinery.Maintenance of body fluid volume homeostasis requires a collaborative interaction of many Na ϩ transport mechanisms. Na ϩ transport in epithelia that line the late distal convoluted tubule, connecting tubule, and collecting tubule relies on apical Na ϩ entry through epithelial Na ϩ channels (ENaC self-inhibition (4, 6 -8). However, detailed elements regarding its mechanism have not been revealed.A logical place to search for structural elements associated with Na ϩ self-inhibition is the large extracellular domain (ECD) that connects the two transmembrane domains (M1 and M2) within each ENaC subunit. The ECD likely exists as well structured subdomains with 16 conserved Cys residues. We recently reported that point mutations at multiple ␣ and ␥ ECD Cys residues blunted Na ϩ self-inhibition, and certain double or triple mutations rendered ENaC insensitive to high concentration of extracellular Na ϩ . These results suggest that multiple Cys residues are required to establish the proper tertiary structure permitting this allosteric regulation (9). In addition, the N-terminal portion of ECD contains ␥His 239 , a previously identified residue critical for Na ϩ self-inhibition, as well as defined protease cleavage sites (4, 10 -12). Various proteases have been shown to regulate ENaC activity, in part, by interfering with Na ϩ self-inhibition (6, 7, 13). The resolved high resolution structure of the chicken acidsensing i...

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Section: Discussionsupporting

confidence: 86%

Novel Determinants of Epithelial Sodium Channel Gating within Extracellular Thumb Domains

Maarouf

Sheng

Chen

et al. 2009

Journal of Biological Chemistry

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“…Furthermore, ligand binding protects the µ and δ receptors against inactivation by the alkylating agent N-ethylmaleimide, suggesting that H223 is in the vicinity of the receptor binding pocket. Alternatively, histidine replacement alters the active conformation of the µ-receptor [27].…”

Section: Evidence For the Interaction Of The El Regions With Opioid Lmentioning

confidence: 99%

The Function of the Extracellular Regions in Opioid Receptor Binding: Insights from Computational Biology

Paterlini¹

2005

CTMC

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Pain management using opioid analgesics strives to achieve three goals: maximum efficacy, minimal risk of tolerance and physical dependence, and negligible side effects. Following the cloning of opioid and nociceptin receptors, novel ligands can be designed to target specific residues of these membrane proteins with the goal of improving efficacy and reducing side effects through selectivity. For the most part, ligand design has focused on binding sites located in the transmembrane region of the receptors, and has ignored the extracellular domains. In this review, we discuss the evidence for the interaction of the extracellular regions with opioids and show how computational biology tools can be used to model these domains for use in drug discovery. A computational model of the kappa-opioid receptor which includes the loop regions is presented. The model combines knowledge-based information, bioinformatics and computational tools to identify regions of the extracellular loop domains that can be targeted by drug design.

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“…Key residues thought to be important for the function of GPCRs are present, such as the DRY motif at alignment positions 189–191 (159, 160) and the conserved Cys-Cys bridge between EL1 and EL2 provided by residues at 165 and 245 (161, 162). Na + is known to regulate the agonist binding of GPCRs and is dependent on an allosteric binding site at the conserved Asp (134) in the TM2 domain (163, 164).…”

Section: The Vertebrate Opioid Receptor Familymentioning

confidence: 99%

The evolution of vertebrate opioid receptors

Stevens¹

2009

Front Biosci

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The proteins that mediate the analgesic and other effects of opioid drugs and endogenous opioid peptides are known as opioid receptors. Opioid receptors consist of a family of four closely-related proteins belonging to the large superfamily of G-protein coupled receptors. The three types of opioid receptors shown unequivocally to mediate analgesia in animal models are the mu (MOR), delta (DOR), and kappa (KOR) opioid receptor proteins. The role of the fourth member of the opioid receptor family, the nociceptin or orphanin FQ receptor (ORL), is not as clear as hyperalgesia, analgesia, and no effect was reported after administration of ORL agonists. There are now cDNA sequences for all four types of opioid receptors that are expressed in the brain of six species from three different classes of vertebrates. This review presents a comparative analysis of vertebrate opioid receptors using bioinformatics and data from recent human genome studies. Results indicate that opioid receptors arose by gene duplication, that there is a vector of opioid receptor divergence, and that MOR shows evidence of rapid evolution.

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Sensitivity of opioid receptor binding to N-substituted maleimides and methanethiosulfonate derivatives

Cited by 15 publications

References 23 publications

Novel Determinants of Epithelial Sodium Channel Gating within Extracellular Thumb Domains

Novel Determinants of Epithelial Sodium Channel Gating within Extracellular Thumb Domains

The Function of the Extracellular Regions in Opioid Receptor Binding: Insights from Computational Biology

The evolution of vertebrate opioid receptors

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