Insulin Receptors, Receptor Antibodies, and the Mechanism of Insulin Action

Kahn, C. Ronald; Baird, Kathleen L.; Flier, J. S.; Grünfeld, Carl; Harmon, Joan T.; Harrison, Len C.; Karlsson, Fredrik; Kasuga, Masato; King, George L.; Lang, Ursula; Podskalny, Judith M.; Obberghen, Emmanuel Van

doi:10.1016/b978-0-12-571137-1.50015-3

Cited by 90 publications

(55 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings suggest that increased D3nf expression may contribute to functional states of altered dopaminergic activity. Collectively, these observations suggest that, in a manner analogous to the way that dimerization plays an important role in the modulation of cell signaling for the homologous insulin-and gonadotropin-releasing hormone receptors (Kahn et al, 1981;Gregory et al, 1982), D3nf dimerization with full-length D3, D2, or D1 receptor could regulate dopamine signaling. Thus, alterations in D3 receptor isoform expression could modulate the effects of dopamine stimulation in altered functional states such as behavioral sensitization.…”

Section: D3 Dopamine Receptor Alternative Splicingmentioning

confidence: 89%

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Richtand

2006

Neuropsychopharmacol

View full text Add to dashboard Cite

Behavioral sensitization, the progressive and enduring augmentation of certain behaviors following repetitive drug use, alters rodent locomotion in a long-standing manner. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. Individual dopamine receptor subtypes have markedly different functional responses to stimulation, with D3 dopamine receptor stimulation inhibiting rodent locomotion. The D3 receptor has highest affinity of the dopamine receptor subtypes for dopamine, and is occupied to a greater degree following stimulant drug administration. D3 receptor activity may be regulated through the expression of an alternatively spliced, truncated receptor isoform (termed 'D3nf') altering receptor localization and function via dimerization with the full-length subunit. The expected physiological response to repetitive drug administration is tolerance. Tolerance of D3 receptor inhibition of locomotion would contribute to sensitization to stimulant drugs. We hypothesize that repetitive D3 receptor stimulation contributes to the development of behavioral sensitization through decreased responsivity of D3-receptor-mediated locomotor inhibition. Increased D3nf expression may direct altered receptor localization and subsequent release of D3-receptormediated inhibition, contributing to the expression of sensitization. These hypotheses follow directly from the affinities of the receptor subtypes for dopamine; dopamine concentrations following stimulant administration; the effects of individual dopamine receptor subtype stimulation on locomotion; and the expected homeostatic response of the system to perturbation by drug. Clarifying these mechanisms underlying sensitization may suggest new interventions for neuropsychiatric conditions in which dopamine plays an important role, including psychosis, drug dependence, and Parkinson's disease. This information may also elucidate a previously unrecognized mechanism regulating receptor trafficking and desensitization.

show abstract

Section: D3 Dopamine Receptor Alternative Splicingmentioning

confidence: 89%

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Richtand

2006

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…It is possible that it plays a role in cellular processes such as receptor affinity regulation, hormone and receptor internalization and signal transmission. These phenomena are well-characterized (for reviews see Kahn et al, 1981;Gammeltoft, 1984), but their molecular mechanism is almost completely unknown. Most likely receptor regulation, internalization and transmembrane signalling are integrated events in insulin action, and receptor autophosphorylation per se is involved in transmission of the insulin message to cellular enzymes and transport carriers.…”

Section: Role Of Receptor Phosphorylation In Insulin Actionmentioning

confidence: 99%

“…It also became clear that receptors mediate proteolytic degradation of insulin, probably via endocytosis of the receptor-bound hormone. These results were primarily based on studies of the interaction of radioiodinated insulin with isolated cells or plasma membranes (for reviews see Kahn et al, 1981;Gammeltoft, 1984). The insulin receptor structure has been elucidated through affinity labelling of receptors by chemical cross-linking with 125I-insulin, biosynthetic or cell-surface labelling of receptor subunits (for reviews see Jacobs&Cuatrecasas, 1981 ;Czech, 1984;VanObberghen, 1984).…”

Section: Introductionmentioning

confidence: 99%

Protein kinase activity of the insulin receptor

Gammeltoft¹,

Obberghen²

1986

Biochemical Journal

139

View full text Add to dashboard Cite

The insulin receptor is an integral membrane glycoprotein (Mr approximately 300,000) composed of two alpha-subunits (Mr approximately 130,000) and two beta-subunits (Mr approximately 95,000) linked by disulphide bonds. This oligomeric structure divides the receptor into two functional domains such that alpha-subunits bind insulin and beta-subunits possess tyrosine kinase activity. The amino acid sequence deduced from cDNA of the single polypeptide chain precursor of human placental insulin receptor revealed that alpha- and beta-subunits consist of 735 and 620 residues, respectively. The alpha-subunit is hydrophilic, disulphide-bonded, glycosylated and probably extracellular. The beta-subunit consists of a short extracellular region which links the alpha-subunit through disulphide bridges, a hydrophobic transmembrane region and a longer cytoplasmic region which is structurally homologous with other tyrosine kinases like the src oncogene product and EGF receptor kinases. The cellular function of insulin receptors is dual: transmembrane signalling and endocytosis of hormone. The binding of insulin to its receptor on the cell membrane induces transfer of signal from extracellular to cytoplasmic receptor domains leading to activation of cell metabolism and growth. In addition, hormone-receptor complexes are internalized leading to intracellular proteolysis of insulin, whereas receptors are recycled to the membrane. These phenomena are kinetically well-characterized, but their molecular mechanisms remain obscure. Insulin receptor in different tissues and animal species are homologous in their structure and function, but show also significant differences regarding size of alpha-subunits, binding kinetics, insulin specificity and receptor-mediated degradation. We suggest that this heterogeneity of receptors may be linked to the diversity in insulin effects on metabolism and growth in various cell types. The purified insulin receptor phosphorylates its own beta-subunit and exogenous protein and peptide substrates on tyrosine residues, a reaction which is insulin-sensitive, Mn2+-dependent and specific for ATP. Tyrosine phosphorylation of the beta-subunit activates receptor kinase activity, and dephosphorylation with alkaline phosphatase deactivates the kinase. In intact cells or impure receptor preparations, a serine kinase is also activated by insulin. The cellular role of two kinase activities associated with the insulin receptor is not known, but we propose that the tyrosine- and serine-specific kinases mediate insulin actions on metabolism and growth either through dual-signalling or sequential pathways.(ABSTRACT TRUNCATED AT 400 WORDS)

show abstract

“…with autoantibodies to the insulin receptor was a kind gift from C.R. Kahn (Joslin Research Laboratory, Boston MA) [9]. The mouse antiserum reacting with H-2b histocompatibility antigens (BlOA cy BIO, no.762) was from the CSEAL-CNRS (Orleans).…”

Section: -L Materialsmentioning

confidence: 99%