Receptors I

Receptors I: Enzyme-Linked Receptors, Cytokine Receptors, and

Ligand-Gated Ion Channels

Enzyme-Linked Receptors

(1) Receptor Tyrosine Kinase – receptors for growth factors (EGF, PDGF) or hormones (insulin)

Structure – transmembrane polypeptide with intrinsic catalytic activity

normally monomeric (insulin is exception) – amino terminus has extracellular binding domain, carboxy terminus is intracellular

Ligand – large polypeptide endocrine/paracrine; growth factors or differentiation signals – binds with veryhigh affinity (10^-9 K_d)

Conformational States

dimerization activates tyr Kinase Domain

criss-cross tyr auto phosphorylation

phosphorylated sites recruit SH2 domain-pp

SIGNAL TRANSDUCTION

Mutated RTK: can be oncogene = a gene that transforms cell into increased proliferative state (cancer)

could be the result of deleted extracellular domain or point mutation

Termination of Signal: Internalization of complex Þ dissociation Þ degradation of ligand/ recycling of receptor to surface

(2) Phosphatases: Ex CD45 (Ligand on plasma membrane of another cell)

(3) Serine/Threonine Kinase: Ex TGF-ß mutation involved in some familial colon cancer cases

(4) Guanylate Cyclase Activity: Ex Atrial Natriuretic Factor (ANF) GTP Þ cGMP (discussed in later lecture)

Cytokine Receptors

Function – autocrine/paracrine regulator of growth and differentiation-includes: Interlukines, Interferon etc.

Structure – multimeric receptor-single transmembrane domain/N-terminal extracellular, C-terminal intracellular

Transduction –

NT-Ligand Gated Ion Channel

Structure – oligomeric complexes of 4-5 protein subunits

(M1-M2), (M2-M3) – have short connecting loops
(M3-M4) – long loop with phosphorylation site by different 2^nd messenger proteins
extracellular N-terminal end is multiply glycosylated with cysteine binding site
C terminus is short

Ligand – small low affinity organic molecules

Cation Channels – Excitatory (Cation flows in Þ depolarization Þ Ý Eo) Ach (nicotinic), glutamate, serotonin, Xcell ATP

Anion Channel – Inhibitory (Anion flows in Þ hyperpolerization Þ ß Eo) GABA and Glycine

These channels can "cross-talk" with G-protein coupled receptors (i.e. acetylcholine muscarinic and nicotinic)

Signal Termination

(1) reduction in concentration of NT – ß affinity means ß [NT] Þ signal termination

(2) desensitization/inactivation of channel – limits signal