Biomedical subjects
H Scherubl
Publications and source records attributed to H Scherubl.
Expression of functional GABAA receptors in cholecystokinin-secreting gut neuroendocrine murine STC-1 cells.
1. Gastrointestinal neuroendocrine (NE) cells synthesize, store and secrete gamma-aminobutyric acid (GABA). Recently, an autocrine-paracrine function of GABA has been proposed for secretion from NE cells. 2. To search for functional GABAA receptors in NE gut cells, we performed whole-cell and perforated-patch-clamp studies in the intestinal cholecystokinin (CCK)-secreting NE cell line STC-1. 3. Application of GABA evoked currents in STC-1 cells. These effects were mimicked by muscimol, an agonist of GABAA receptors, and blocked by picrotoxin or bicuculline, antagonists of GABAA receptors. The GABA- or muscimol-activated currents reversed near 0 mV, which under the recording conditions used was consistent with the activation of the GABAA receptor-Cl- channel complex. 4. In contrast to the effect on most neurons, GABA as well as muscimol led to a (reversible) depolarization of the membrane potential of STC-1 cells. Membrane depolarization in turn activated voltage-gated Ca2+ channels and increased intracellular Ca2+ concentrations in STC-1 cells. 5. In accordance with the observed membrane depolarization and activation of voltage-gated Ca2+ channels, both GABA and muscimol stimulated Ca2+-dependent CCK release. In contrast, bicuculline inhibited the GABA-induced secretion of CCK. 6. Using the reverse transcription-polymerase chain reaction (RT-PCR), mRNA of the GABAA receptor subunits alpha2, alpha3, alpha5, beta1, beta3 and delta could be detected in STC-1 cells. 7. In summary, we have shown that the CCK-secreting gut NE cell line STC-1 expresses functional GABAA receptors and that GABA stimulates CCK release. Thus, GABA is involved in the fine tuning of CCK secretion from the gut NE cell line STC-1.
Gastroenteropancreatic tumor imaging with somatostatin receptor scintigraphy.
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Extracellular Ca2+ sensing in C-cells and parathyroid cells.
An essential function of C-cells and parathyroid cells is to monitor the extracellular Ca2+ concentration. The Ca(2+)-dependent secretion of calcitonin (CT) and parathyroid hormone is known to be mediated by corresponding changes in the intracellular Ca2+ concentration. To address the question of whether Ca2+ influx through voltage-dependent Ca2+ channels couples the extracellular to the intracellular Ca2+, we applied the patch clamp technique to C-cells of the rMTC 44-2 cell line and to parathyroid cells of the PT-r cell line. The rMTC cells displayed dihydropyridine-sensitive, voltage-dependent, high-threshold Ca2+ channels which allowed ion influx even at the resting potential of about -40 mV. Increases of the concentration of the extracellular divalent cation or adding the Ca2+ channel agonist Bay K 8644 stimulated the steady state ion influx. In contrast, PT-r cells exhibited only fast inactivating, low-threshold Ca2+ channel currents with no steady state conductivity for Ca2+ at the resting potential of around -40 mV. We conclude that dihydropyridine-sensitive Ca2+ channels allow steady state transmembranous Ca2+ influx in C-cells, thereby increasing the cytosolic Ca2+ and CT secretion. Parathyroid cells, however, lack long-lasting Ca2+ channel currents and obviously sense the extracellular Ca2+ concentration by other mechanisms.
Somatostatin acts via a pertussis toxin-sensitive mechanism on calcitonin secretion in C-cells.
The effect of the somatostatin analog octreotide on cAMP-mediated calcitonin (CT) secretion and cAMP accumulation in C-cells was investigated. Glucagon stimulated cAMP accumulation and CT secretion with a maximal effect at a concentration of 10(-6) M. The cAMP antagonist RpcAMPs blocked the glucagon-induced CT secretion down to control levels. Therefore, no other second messengers seem to be involved in glucagon-stimulated CT secretion. Octreotide in increasing doses (10(-9) to 10(-6) M) inhibited cAMP accumulation and CT secretion with a maximal effect at a concentration of 10(-7) (40% and 29% of control values, respectively). Pretreatment of the cells with 100 ng/mL pertussis toxin for 24 hours abolished the inhibitory effect of octreotide on cAMP accumulation and CT secretion (82% and 58% of control values, respectively). Similar results were obtained under the influence of the phosphodiesterase inhibitor IBMX. Therefore, we conclude that somatostatin modulates adenylate cyclase-coupled CT secretion in C-cells via a pertussis toxin-sensitive G-protein possibly in an autocrine/paracrine way.
Modulation of calcitonin secretion by modification of calcium channels?
Voltage-dependent calcium channels (VDCC) regulating Ca++ influx through the cellular plasma membrane play a major role in the Ca(++)-induced calcitonin (CT) secretion. Using rat C-cells (rMTC 6-23 cell line), we have studied the effect of repetitive stimulation by either Ca++ (2 mM) or glucagon (10 microM) or epinephrine (10 microM) on CT secretion. Following a Ca(++)-induced initial rise, CT release declined to basal levels after about four hours despite high Ca++; addition of 10 microM glucagon to the "Ca++ desensitized C-cells" yielded the normal stimulatory effect of glucagon on CT release. Repetitive stimulation with glucagon showed a constant stimulatory action over an eight-hour period. In contrast, repetitive stimulation with 10 microM epinephrine caused an initial rise followed by a gradual decline of CT release over six hours. The observed desensitization of Ca(++)-induced CT secretion may be due to a modification of VDCC in C-cells. Whether or not the desensitization of epinephrine-induced CT release occurs independently of the regulation of VDCC remains unclear.