A. Interactions with Target Tissues
Glucagon secretion is stimulated by a fall in the blood glucose level or a rise in the blood levels of free fatty acids or certain amino acids (see Table 7-8). Most of the biological consequences of glucagon lead to an increase in the blood level of glucose. Virtually all of the glucagon secreted by the pancreatic a-cell is sequestered by the hepatocyte cells of the liver; thus, the extrahepatic blood levels of glucagon are quite low.
Glucagon elicits its plasma biological responses through interaction with a membrane receptor, which leads to an increase in intracellular [Ca2+] and an elevation of cAMP. Figure 1-6 describes the cascade mechanism linking the occupancy of the glucagon receptor to the stimulation of glycogenolysis. The second messenger, cyclic AMP, then is the intracellular initiator of specific responses. Glucagon has a high affinity for its liver cell membrane receptor; the Kd is 4 X 10 9 M.
Insulin is the chief hormone controlling intermediary metabolism. It affects virtually every tissue in the body, but principally liver, muscle, and adipose tissue. Its short-term effects are to reduce blood glucose and to conserve body fuel supplies. There are also a number of effects of insulin on the regulation of gene transcription and cell replication. Thus, an understanding of the mode of action of insulin is complex; Figure 728 presents an introductory schematic diagram of the signal transduction events that link the formation of an insulin-receptor complex to the generation of its many biological responses.
The number of insulin receptors in insulin target cells ranges from less than 100 to more than 200,000 per cell; the highest concentrations of the insulin receptor are on hepatocytes and adipocytes. The insulin receptor is a heterotetrameric transmembrane glycoprotein of 350-440 kDa. It is composed of two a-subunits
(135 kDa) linked by disulfide bonds to two /3-subunits (95 kDa). There is uncertainty whether the insulin receptor binds one or two insulin molecules. As shown in Figure 7-29, each a-subunit appears to contain an insulin-binding domain; however, when one site is occupied, it induces negative cooperativity for the second insulin-binding site.
Interestingly, like insulin, which consists of A and B chains derived from a common precursor (see Figure 7-13), both subunits of the insulin receptor are derived from a single amino acid chain proreceptor. Also, a variety of amino acid substitution mutations have been identified in both the a- and /3-subunits of the insulin receptor present in patients with severe insulin resistance. Occupancy of the receptor initiates a complex series of response cascades that involve over 50 proteins-enzymes. The response cascades can be classified at three levels (see Figure 7-30). Level I describes the immediate consequences of occupancy of the ar subunit of the insulin receptor and includes activation of the receptor's tyrosine kinase, which catalyzes the phosphorylation of the cytoplasmic protein /nsulin Receptor Substrate-1; this protein then interacts with several other proteins, including PI 3-kinase and SH2-GRB2. Level II involves a series of serine and threonine kinases and phosphatases, particularly the enzymes MAP kinase4 and RAF kinase. These latter two kinases then initiate a cascade of phosphorylation and dephos-phorylation steps that are coupled to both the cytoplasmic and nuclear responses described in level III. In level III, the principal cytoplasmic responses are the regulation of glycogen synthesis via glycogen synthase and the regulation of glucose transporter translocation. The nuclear responses include stimulation of gene expression, cell growth, and protein synthesis.
The time scale of response to insulin ranges from immediate (occurring within seconds to minutes after occupancy of the insulin receptor), to intermediate (minutes to hours), to long-term (many hours to days).
As emphasized in Figure 7-28, the first step of signal transduction initiated by the occupied insulin receptor is the activation of its tyrosine kinase activity when the a-subunit-binding domain is occupied by insulin. The key substrate for the tyrosine kinase activity has been identified as being a 131-kDa intracellular protein termed IRS-1. IRS-1 is essential for some, if not all, of insulin's biological actions. The most noteworthy feature of IRS-1 is that it possesses 21 potential tyrosine phosphorylation sites; 6 sites
4 The serine-threonine kinase was originally named because it phosphorylates microtubule-associated protein (MAP). The enzyme is now known as MAP kinase, because it is stimulated by many mitogens, or as extracellular signal-related kinase (ERK), because it is regulated by a variety of extracellular ligands.
Hormones, Second Edition
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