Secretion defects

Jansen PL, van Klinken JW, van Gelder M, Ottenhoff R, Elferink RP (1993) Preserved organic anion transport in mutant TR-rats with a hepatobiliary secretion defect. Am J Physiol 265 G445-G452. 

Studies by Scmtton et. al. and Stormoiken and his associates, have shown compromised functional response to epinephrine in apparently normal individuals (52,53). Weiss et. al. have described secretion defects from patients with bleeding disorders (54). White et. al. have followed functional response of platelets of patients with diabetes and Hermasky-Pudlak Syndrome (HPS) whose platelets lack dense bodies. Platelets of patients with HPS exhibit compromised response to the action of agonists (55). Hardisty et. al., and Ware and associates, have provided further evidence for altered signal transduction mechanisms. These and other studies seem to suggest that an impaired intracellular calcium flux may be the chief cause of platelet dysfunction (56-58, discussed in other chapters). 

Ran AK, Willis J, Hassell B, Dangdmaier C, Holmsen H, Smith JB. Platdet-sictivating factor is a weak platelet atgomsb evidence fiomnonnal human platelets and platelets with congenital secretic defects. AmerJHematol 1984 17 153-165... 

Signal transduction defects primary secretion defects)... 

Defects in Platelet Signal Transduction (Primary Secretion Defects)... 

Koike K, Rao AK,HcdmsenH,hAiefler PM. Platelet secretion defect in patients with die attention deficit disorder and essy bruising. Blood 1984 63 427-433. 

RaoAK,KowildcaMA,Disa J. Impaired cytoplasmic ionized calcium mobilization in inherited platelet secretion defects. Blood 1989 74 664-672. 

Synthesis of SecA is regulated in response to protein export (Oliver and Beckwith, 1982b). When export is inhibited, the production of SecA increases at least 10-fold to compensate for the secretion defect. Oliver and Beckwith (1982b) have speculated that the presence of precursors of secreted proteins in the cytoplasm could serve as a regulator of the expression of proteins needed for synthesis. 

S. Ferro-Novick and J. Beckwith, personal communication), can suppress the secretion defect of a secA mutant (Ferro-Novick et al., 1984c). The phenotype of a temperature-sensitive secC mutant is similar to that of a secA strain. At the nonpermissive temperature, synthesis of exported proteins is blocked. The synthesis of MBP can be restored in secC mutants by mutations in the hydrophobic core of its signal sequence. The new insights into SecA mutants (Strauch et al., 1986) cloud the interpretation of thise results. 

Type 2 Diabetes Mellitus This is the most prevalent form of diabetes and is characterized by both an insulin secretion defect and insulin resistance. Maturity-onset diabetes of the young (MODY), attributable to mutations of the glucose kinase gene (discussed earlier), may also be classified as type 2 diabetes mellitus. Obesity is a contributory factor and may predispose to insulin resistance with eventual development of type 2 diabetes mellitus. The precise mechanism by which obesity leads to insulin resistance in the target tissues is not understood. However, in several animal models (e.g., ob/ob mouse, db/db mouse) mutations have been identified that cause both obesity and diabetes mellitus. Unlike type 1 diabetes mellitus, type 2 is not an autoimmune disease. Studies with monozygotic twins have revealed a 90% concordance rate for type 2 diabetes mellitus, suggesting the involvement of genetic factors in the development of the disease. 

Li, Y., Moir, R. D., Sethy-Coraci, I. K., Warner, J. R., and Willis, I. M. (2000). Repression of ribosome and tRNA synthesis in secretion-defective cells is signaled by a novel branch of the cell integrity pathway. Mol. Cell. Biol. 20, 3843-3851. 

Diabetes mellitus (DM) is characterised by hyperglycaemia due to defective insulin secretion, defective insulin action or both. The global prevalence in 2010 is 285 million cases and this is projected to be 439 million in 2030. The main types are type 1 DM (TIDM) and type 2 DM (T2DM). There is also gestational DM and other unusual types such as maturity-onset diabetes of the young (MODY). 

Type 2 diabetes is a heterogeneous and progressive endocrine disorder associated with insulin resistance (impaired insulin action) and defective function of the insulin-secreting (3-cells in the pancreatic islets of Langerhans. These endocrine disorders give rise to widespread metabolic disturbances epitomised by hyperglycaemia. The present classes of antidiabetic agents other than insulin act to either increase insulin secretion, improve insulin action, slow the rate of intestinal... 

Asthma is a complex respiratory disorder that involves mast cell degranulation, mucous secretions, and smooth muscle hypertrophy and hyperresponsiveness. Smooth muscle hyperresponsiveness has suggested some defect in the regulation of smooth muscle contractility. Therefore, a number of studies concerning asthma have centered on whether alterations in the regulation of smooth muscle contraction (Figure 4) are responsible for hyperactivity in asthmatic airway smooth muscle. 

It has been known for many years that antimuscarinic drugs like hyoscine, which enter the brain, cause amnesia when used clinically, e.g. pre-operatively, to reduce bronchial secretions. In experimental studies in both humans and animals they disrupt both the acquisition and the performance of learned behaviour. Anti-cholinestrase drugs have the opposite effect. It is by no means certain, however, that the memory defects induced by antimuscarinics are identical to those seen in AzD. 

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), a chloride (CF) channel characterised by chloride permeability and secretion, and also by the regulation of other epithelial ion channels (Eidelman et al, 2001). Mutations in the CFTR gene lead to an impaired or absent Cl conductance in the epithelial apical membrane, which leads to defective Cl secretion and absorption across the epithelium. Genistein (Illek et al, 1995 Weinreich et al, 1997) and other flavonoids (Illek and Fisher, 1998) have been shown, in different animal and tissue models, to activate wild-type CFTR and CFTR mutants by (Eidelman et al, 2001 Roomans, 2001 Suaud et al, 2002) ... 

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