Serotonin (5-hydroxytryptamine)


Serotonin (5-hydroxytryptamine)


I 2 ch2

COO" Glutamate ple neurons. The cell responds with an action potential only if the integrated input adds up to a net depolarization of sufficient size.

The receptor channels for acetylcholine, glycine, glutamate, and y-aminobutyric acid (GABA) are gated by extracellular ligands. Intracellular second messengers—such as cAMP, cGMP (3',5'-cyclic GMP, a close analog of cAMP), IP3 (inositol 1,4,5-trisphosphate), Ca2 + , and ATP—regulate ion channels of another class, which, as we shall see in Section 12.7, participate in the sensory transductions of vision, olfaction, and gustation.

SUMMARY 12.2 Gated Ion Channels

■ Ion channels gated by ligands or membrane potential are central to signaling in neurons and other cells.

■ The acetylcholine receptor of neurons and myocytes is a ligand-gated ion channel.

■ The voltage-gated Na+ and K+ channels of neuronal membranes carry the action potential along the axon as a wave of depolarization (Na+ influx) followed by repolarization (K+ efflux).

■ The arrival of an action potential triggers neurotransmitter release from the presynaptic cell. The neurotransmitter (acetylcholine, for example) diffuses to the postsynaptic cell, binds to specific receptors in the plasma membrane, and triggers a change in Vm.

12.3 Receptor Enzymes

A fundamentally different mechanism of signal trans-duction is carried out by the receptor enzymes. These proteins have a ligand-binding domain on the extracellular surface of the plasma membrane and an enzyme active site on the cytosolic side, with the two domains connected by a single transmembrane segment. Commonly, the receptor enzyme is a protein kinase that phosphorylates Tyr residues in specific target proteins; the insulin receptor is the prototype for this group. In plants, the protein kinase of receptors is specific for Ser or Thr residues. Other receptor enzymes synthesize the intracellular second messenger cGMP in response to extracellular signals. The receptor for atrial natriuretic factor is typical of this type.

The Insulin Receptor Is a Tyrosine-Specific Protein Kinase

Insulin regulates both metabolism and gene expression: the insulin signal passes from the plasma membrane receptor to insulin-sensitive metabolic enzymes and to the nucleus, where it stimulates the transcription of specific genes. The active insulin receptor consists of two identical a chains protruding from the outer face of the plasma membrane and two transmembrane 3 subunits with their carboxyl termini protruding into the cytosol (Fig. 12-6, step d). The a chains contain the insulin-binding domain, and the intracellular domains of the 3 chains contain the protein kinase activity that transfers a phosphoryl group from ATP to the hydroxyl group of Tyr residues in specific target proteins. Signaling through the insulin receptor begins (step (J)) when binding of insulin to the a chains activates the Tyr ki-nase activity of the 3 chains, and each a3 monomer phosphorylates three critical Tyr residues near the car-boxyl terminus of the 3 chain of its partner in the dimer. This autophosphorylation opens up the active site so that the enzyme can phosphorylate Tyr residues of other target proteins (Fig. 12-7).

One of these target proteins (Fig. 12-6, step ©) is insulin receptor substrate-1 (IRS-1). Once phosphory-lated on its Tyr residues, IRS-1 becomes the point of nu-cleation for a complex of proteins (step @) that carry the message from the insulin receptor to end targets in the cytosol and nucleus, through a long series of intermediate proteins. First, a (P-Tyr residue in IRS-1 is bound by the SH2 domain of the protein Grb2. (SH2 is an abbreviation of «Src homology 2; the sequences of SH2 domains are similar to a domain in another protein Tyr kinase, Src (pronounced sark).) A number of signaling proteins contain SH2 domains, all of which bind <3>-Tyr residues in a protein partner. Grb2 also contains a second protein-binding domain, SH3, that binds to regions rich in Pro residues. Grb2 binds to a proline-rich region of Sos, recruiting Sos to the growing receptor complex. When bound to Grb2, Sos catalyzes the replacement of bound GDP by GTP on Ras, one of a family of guanosine nucleotide-binding proteins (G proteins) that mediate a wide variety of signal transductions (Section 12.4). When GTP is bound, Ras can activate a protein kinase, Raf-1 (step @), the first of three protein kinases—Raf-1, MEK, and ERK—that form a cascade in which each kinase activates the next by phosphoryla-tion (step ©). The protein kinase ERK is activated by phosphorylation of both a Thr and a Tyr residue. When activated, it mediates some of the biological effects of insulin by entering the nucleus and phosphorylating proteins such as Elk1, which modulates the transcription of about 100 insulin-regulated genes (step ©).

The proteins Raf-1, MEK, and ERK are members of three larger families, for which several nomenclatures are employed. ERK is a member of the MAPK family (mitogen-activated protein kinases; mitogens are signals that act from outside the cell to induce mitosis and cell division). Soon after discovery of the first MAPK, that enzyme was found to be activated by another protein kinase, which came to be called MAP kinase kinase (MEK


Insulin receptor binds insulin and undergoes autophosphorylation on its carboxyl-terminal Tyr residues.

Insulin receptor phosphorylates IRS-1 on its Tyr residues.


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