Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide

Serotonin can produce multiple, contradictory modulatory effects on strength of synaptic transmission in both vertebrate and invertebrate nerve circuits. In crayfish, serotonin (5-HT) can both facilitate and depress transmission to lateral giant escape command neurons; however, which effect is manifest during application, as well as the sign and duration of effects that may continue long after 5-HT washout, may depend on history of application as well as on concentration. We report that protein kinase A (PKA) signaling is essential to the production of facilitation but depression is mediated by non-cAMP/PKA signaling pathways. However, we unexpectedly found that PKA activity is essential for the decay of depression when serotonin is washed out. This, and evidence from the effects of a variety of serotonin application regimens, suggest that facilitatory and depressive states coexist and compete and that the decay of each is dependent on stimulation by the other. A computational model that incorporates these assumptions can account for and rationalize the varied effects of a wide range of serotonin application regimens.

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Mechanisms of PTH-induced rise in cytosolic calcium in adult rat hepatocytes

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1994.267.5.g754 ◽

1994 ◽

Vol 267 (5) ◽

pp. G754-G763 ◽

Cited By ~ 1

Author(s):

M. Klin ◽

M. Smogorzewski ◽

H. Khilnani ◽

M. Michnowska ◽

S. G. Massry

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Protein Kinase A ◽

G Protein ◽

Cytosolic Calcium ◽

Amino Terminal ◽

Kinase C ◽

Dose Dependent ◽

Kinase A ◽

Stimulation Of

Available data indicate that the liver is a target organ for parathyroid hormone (PTH) and that this effect is most likely mediated by PTH-induced calcium entry into hepatocytes. The present study examined the effects of both PTH-(1-84) and its amino-terminal fragment [PTH-(1-34)] on cytosolic calcium concentration ([Ca2+]i) of hepatocytes and explored the cellular pathways that mediate this potential action of PTH. Both moieties of PTH produced a dose-dependent rise in [Ca2+]i, but the effect of PTH-(1-84) was greater (P < 0.01) than an equimolar amount of PTH-(1-34). This effect required calcium in the medium and was totally [PTH-(1-34)] or partially [PTH-(1-84)] blocked by PTH antagonist ([Nle8,18,Tyr34]bPTH-(7-34)-NH2] and by verapamil or nifedipine. Sodium or chloride channel blockers did not modify this effect. 12-O-tetradecanoylphorbol 13-acetate (TPA), an activator of protein kinase C, dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), and G protein activator also produced a dose-dependent rise in [Ca2+]i. Staurosporine abolished the effect of TPA, and both staurosporine and calphostin C partially inhibited the effect of PTH. Staurosporine and verapamil together produced greater inhibition of PTH action than each alone. Rp-cAMP, a competitive inhibitor of cAMP binding to the R subunit of protein kinase A, and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), a protein kinase A inhibitor, blocked the effect of both DBcAMP and PTH, but the effect of these agents was greater (P < 0.01) on DBcAMP action. G protein inhibitor and pertussis toxin partially blocked the action of PTH. The data indicate that 1) PTH increases [Ca2+]i of hepatocytes; 2) this action of the hormone is receptor mediated; 3) the predominant pathway for this PTH action is the stimulation of a G protein-adenylate cyclase-cAMP system, which then leads to stimulation of a calcium transport system inhibitable by verapamil or nifedipine or activation of L-type calcium channels; 4) activation of protein kinase C is also involved; and 5) the PTH-induced rise in [Ca2+]i is due, in major parts, to movement of extracellular calcium into the cell.

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