SS is found in neurons and neuroendocrine cells in the brain, gut and pancreas. SS acts on a family of 5 different SS receptors. These receptors for SS are coupled to Gi causing an inhibition of adenylyl cyclase and therefore a reduction of cAMP formation. SS also causes inhibition of voltage-gated Ca2+ channels activation of potassium ion channels and activation of phosphotyrosine phosphatases. Some of the actions of SS are therefore the reverse of GHRH and would be expected to hyperpolarize the somatotrope cells and reduce spontaneous action potentials. This would be expected to reduce cytosolic Ca2+ and therefore discharge of GH from the secretory vesicles. There may, however, be additional inhibitory effects of SS to reduce GH release that are not dependent on reducing cytosolic Ca2+ (Yunker and Chang, 2004). The SS receptors most important for regulating GH secretion are SSTR2 and SSTR5. The secretions of GHRH and of SS are both under the control of the Central Nervous System so that various stresses can increase GH in plasma. Bursts of GH secretion occur during sleep. SS is found: in the hypothalamus; in D (r) cells of pancreatic islets; in the gastro-intestinal mucosa; and in C cells (parfollicular cells) of the thyroid gland. The major form of SS (at least in the context of the hypothalamus) is a tetradecapeptide (14 amino acids, SS-14), but there is also amino terminal extended form containing 28 amino acids (somatostatin-28), predominantly in the gut. SS is formed from a larger precursor peptide of approximately 100 amino acids (see Benoit et al, 1990; Jenecka et al, 2001). SS-14 contains one disulphide bridge between two cysteines. SS secretion is increased by increased levels of GH and of Insulin-like-growth-factor-1 (IGF-1, see below), as part of a negative feedback pathway. In addition to inhibiting GH secretion, SS also has an important inhibitory influence on other hormones, growth factors and cytokines that include: TSH from the pituitary gland; gastrin, motilin, VIP, gilectin and gastrointestinal peptide from the gut; insulin, glucagons and pancreatic polypeptide from the pancreas. Somatostatin analogues (such the octopeptide, octreotide) are used to treat the unwanted growth in acromegaly (for example as a consequence of excessive GH secretion by an adenoma tumor). Octreotide binds preferentially to SSTR-2 and SSTR-5 receptors (see Moller et al, 2003). SSmimetics are considered for eye diseases associated with excessive proliferation and inflammation and systemic diseases associated with inflammation, such as rheumatoid arthritis. Other recent evidence for an involvement of SS in inflammation is provided by Abdel Salam (2002). 3.8
Actions of Growth Hormone (GH) The major actions of GH are a stimulation of bone and muscle formation. Bone growth is promoted by effects that include differentiation of chodrocytes and osteoblasts that are essential for bone formation. In the case of muscle, GH causes differentiation of the myoblasts that are the precursors of muscle fibres, and also promotes an increase in muscle mass. GH also has a potent anti-insulin action on liver and at peripheral sites such as adipocytes and muscle. GH has been implicated in the development and function of the immune system (see below). The actions of GH are both direct (influencing tissues by an action on GH receptors) or indirect (by stimulation of the production of additional growth factors, predominantly in the liver, with subsequent action of the growth factors on growth factor receptors in the tissues). Direct actions of GH include the following: reduced glucose transport and metabolism (with a reduction in insulin receptors); effects on adipocytes to increase lipolysis (with a localised decrease in adipose tissue, and a release of free fatty acids that then provide an energy source for muscle); increased amino acid transport (into muscle, liver and adipose cells); increased protein synthesis (as a consequence of increases in transcription and translation, for example in the liver); actions on hepatocytes to stimulate gluconeogenesis; and increased fibroblast differentiation that leads to formation of chondrocyte, osteoblast and adipocyte formation. The direct effects of GH generally antagonise those of insulin, giving rise to diabetogenic properties of GH; the direct effects also tend to show synergy with those of cortisol. The growth promoting effects of GH are largely mediated by insulin-like-growth-factor 1 (IGF-1), which is predominantly formed in liver but is also produced locally in many tissues critical for growth. Major effects of IGF-1 produced in the liver are growth promotion of bones and increases in muscle mass. An example of additional GH stimulated local production of IGF-1 is in bone where autocrine and paracrine actions of the
35