Impaired receptors

G-protein-coupled receptor kinases (GRKs) are a family of enzymes that catalyze the phosphorylation of threonine or serine residues on G-protein-coupled receptors. Characteristically, GRKs only phosphorylate the ligand-activated form of the receptors. Phosphorylation by GRKs usually leads to impaired receptor/G-protein coupling. 

An individual can also become insulin resistant because of the development of antibodies gainst insulin. These patients have impaired receptor function and become so unresponsive to insulin that the daily dose requirement may be in excess of500 units per day (U/ d), rather than the usual 40 to 60 U/d. High-potency insulin in a concentrated form (U500 see the Summary Drug Table Insulin Preparations) is used for patients requiring more than 200 U/d. 

Fawell SE, White R, Hoare S, Sydenham M, Page M, Parker MG (1990) Inhibition of estrogen receptor-DNA binding by the pure antiestrogen ICI 164,384 appears to be mediated by impaired receptor dimerization. Proc Natl Acad Sci USA 87 6883-6887... 

However it was later shown that fumonisin B1 treatment does not impair receptor- or dmg-induced apoptosis (Jaffrezou et al 1996), strenghtening the notion that sphingomyelin breakdown plays the major part in the generation of the biologically relevant ceramide. 

Befort, K., FiUiol, D., Decaillot, F. M., Gaveiiaux-Ruff, C., Hoehe, M. R., and Kieffer, B. L. (2001) A single nucleotide polymorphic mutation in the human mu-opioid receptor severely impairs receptor signahng. J. Biol. Chem. 276, 3130-3137. 

Grishina, G., and Berlot, C. H. (1998). Mutations at the domain interface of GOT impair receptor-mediated activation by altering receptor and guanine nucleotide binding. / Biol. Chem. 273, 15053-15060. 

Warner, D. R., and Weinstein, L. S. (1999). A mutation in the heterotrimeric stimulatory guanine nucleotide binding protein a-subunit with impaired receptor-mediated activation because of elevated GTPase activity. Proc. Natl. Acad. Sci. USA... 

Defects of LDL receptors underlie this disorder. Some individuals have combined heterozygosity for alleles producing nonfunctional and kinetically impaired receptors. Levels of LDL in compliant heterozygous patients can be normalized with combined drug regimens (Figure 35-2). Those whose receptors retain even minimal function may partially respond to resins or reductase inhibitors. Niacin and atorvastatin may benefit patients with no receptor function. 

Monnier C, Dode C, Fabre L et al (2009) PROKR2 missense mutations associated with Kallmann syndrome impair receptor signalling activity. Hum Mol Genet 18 75-81... 

Unclear impaired receptor affinity, and possibly decreased expression... 

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