Stimulus-secretion

Ionized calcium is an important regulator of a variety of cellular processes, including muscle contraction, stimulus-secretion coupling, the blood clotting cascade, enzyme activity, and membrane excitability. It is also an intracellular messenger of hormone action. 

Pasti L, Zonta M, Pozzan T, Vicini S, Carmignoto G (2001) Cytosolic calcium oscillations in astrocytes may regulate exocytotic release of glutamate. J Neurosci 21 477 84 Fenner R, Neher E (1988) The role of calcium in stimulus-secretion coupling in excitable and non-excitable cells. J Exp Biol 139 329-345... 

While this chapter is concerned primarily with the neurochemical mechanisms which bring about and control impulse-evoked release of neurotransmitter, some of the methods used to measure transmitter release are described first. This is because important findings have emerged from studies of the effects of nerve stimulation on gross changes in transmitter release and intraneuronal stores. The actual processes that link neuronal excitation and release of transmitter from nerve terminals have been studied only relatively recently. The neurochemical basis of this stimulus-secretion coupling, which is still not fully understood, is described next. The final sections will deal with evidence that, under certain conditions, appreciable amounts of transmitter can be released through Ca +-independent mechanisms which do not depend on neuronal activation. 

Clearly, the most studied aspect of stimulus-secretion coupling is the requirement for calcium. That Ca ions are essential for many cellular processes has been known since the days of Sidney Ringer [178], The eloquent studies of Douglas and his collaborators [179, 180] and others [181] firmly established the necessity for Ca in exocytotic secretion and set forth the notion that an increase in the level of free intracellular Ca, [Ca2+]j was responsible for initiating exocytosis. Evidence for increases in the level of intracellular free Ca as prerequisite for initiating exocytosis by cell surface stimulation is now available from studies using a variety of systems [181-183]. 

Another aspect of stimulus-secretion coupling in the mast cell in which specific peptides and compound 48/80 have been studied is the phosphorylation of specific protein bands in response to stimulation [211-214], In these experiments mast cells were pre-labelled with 32P and stimulated, and... 

Smith, R. J., and Ignarrr), L. J. (1975). Bioregulation of lysosomal enzyme. secretion from human neutrophils Roles of cyclic GMP and calcium in stimulus-secretion coupling. Proc. Natl. Acad. Sci. U.S.A. 72, 108-112. 

Calcium channel blockers minimally interfere with stimulus-secretion coupling in glands and nerve endings because of differences between calcium channel type and sensitivity in different tissues. Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina. 

Petersen OH, Ueda N Pancreatic acinar cells The role of calcium in stimulus-secretion coupling. J Physiol 1976 254 583-606. 

TJam-deficient mice (/ cell-specific Tfam knockout) MtDNA depletion, respiratory chain deficiency Mitochondrial diabetes, impaired stimulus-secretion coupling in f cells in young mice, loss of f cells in older mice S12... 

Douglas WW. 1968. Stimulus-secretion coupling The concept and clues from chromaffin and other cells. Brit J Pharmacol 34 451-474. 

Ca2+ plays a major role in the stimulus-secretion coupling of a variety of cells, including neurons, muscle cells or endocrine glands [63]. In order to be accepted as a second messenger, Ca2+ must fulfill certain requirements [64] a) removal of extracellular Ca2+ must result in an arrest of LH secretion b) the gonadotropes should respond to Ca2+ influx with LH release even in the absence of GnRH c) GnRH should provoke the translocation of Ca2+ into specific intracellular sites of action that can be related to LH release. 

Secretion is the opposite process to that of absorption. In response to various stimuli, crypt cells actively transport chloride into the gut lumen and sodium and water follow. This stimulus-secretion coupling is modulated by cyclic AMP and GMP, calcium, prostaglandins and leukotrienes. 

Cockcroft, S., Howell, T.W. and Gomperts, B.D. (1987). Two G proteins act in series to control stimulus-secretion coupling in mast cells use of neomycin to distinguish between G-proteins controlling polyphosphoinositide phosphodiesterase and exocytosis. J. Cell Biol., 105, 2745-2750. 

Wollheim CB, Regazzi R (1990) Protein kinase C in insulin releasing cells. Putative role in stimulus secretion coupling. In FEBS Lett. 268 376-80. 

Lakhlani PP, Lovinger DM, Limbird LE. Genetic evidence for involvement of multiple effector systems in a2A-adrenergic receptor inhibition of stimulus-secretion coupling. Mol Pharmacol 1996 50 96-103. 

It is commonly agreed that cytosolic Ca2+ serves as a second messenger in stimulus-secretion coupling of insulin release (for a review see Heilman et al., 1992). 

As discussed above, protein phosphorylation caused by CaCaMk, PKA and PKC may induce a variety of functions in the machinery of stimulus-secretion coupling. This, however, implies that to keep the system functional for regulation, dephosphorylations must also take place. Dephosphorylations in general are the result of phosphatase activity. To date, little is known about the function of such phosphatases in insulin-producing cells, or whether they are regulated. 

Fig. 20. Hypothetical model of how insulin secretion is regulated. The most important event is the depolarization of the B-cell which causes Ca"+ influx along L-type Ca2+ channels and subsequent increase in cytosolic Ca"+. Depolarization is produced by nutrient (glucose) metabolism via an increase in B-cell ATP and/or ATP/ADP ratio which closes KAXP channels. Also, sulphonylureas, at a distinct location, close KATP channels. The increase in [Ca2+]j activates CaCaMK. Ca2+ uptake appears to be modulated by nutrient metabolism (redox state of NAD(P)H and GSH). Insulin release in response to depolarization is also modulated by factors affecting PLC and adenylate cyclase. Here, production of IP3 leads to release of stored Ca2+ from the endoplasmic reticiulum. DAG activates PKC whereas cAMP activates PKA. CaMK, PKC and PKA cause protein phosphorylations which finally cause granule movement and exocytosis. But there will also be other effects of phosphorylations related to stimulus-secretion coupling, e.g. a possible interaction with voltage-dependent Ca2+ channels.

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