Dataset Information

Cyclic AMP and calcium signaling are involved in antipsychotic-induced diabetogenic effects in isolated pancreatic β cells of CD1 mice.

ABSTRACT:

Objectives

Antipsychotics (APs) are medications used for different psychological disorders. They can introduce diabetogenic effects through different mechanisms, including cyclic adenosine monophosphate (cAMP) and calcium (Ca²⁺) signaling pathways. However, this effect is poorly understood. Therefore, this study aimed to evaluate the effect of three widely used APs (chlorpromazine, haloperidol, and clozapine) on cAMP and Ca²⁺ signaling.

Methods

The local bioethics committee of Northern Border University approved the study. Pancreatic β-cells were isolated from male CD1 mice, and three drug stock solutions were made in different concentrations (0.1, 1, 10, and 100 μM). The levels of glucose-stimulated insulin secretion (GSIS) and cAMP as well as the activities of adenylyl cyclase (AC), cAMP-dependent protein kinase (PKA), guanine-nucleotide exchange protein activated by cAMP (Epac 1 and 2), Ca²⁺ mobilization, and Ca²⁺/calmodulin kinase II (CaMKII) were then determined using different methods.

Results

APs were found to be cytotoxic to pancreatic β cells and caused a parallel and significant decrease in GSIS. APs significantly reduced the levels of cAMP in the treated cells, with an associated reduction in ATP production, CaMKII, PKA, and transmembrane AC activities as well as Ca²⁺ mobilization to variable extents. In addition, the gene expression results showed that APs significantly decreased the expression of both the active subunits AC1 and AC8, the PKA α and β subunits, Epac1 and Epac2 as well as the four main subunits of CaMKII to variable extents.

Conclusion

AP-induced alterations in the cAMP and Ca²⁺ signaling pathways can play a significant role in their diabetogenic potential.

SUBMITTER: Al-Ghafari A

PROVIDER: S-EPMC9441645 | biostudies-literature | 2022 Sep-Oct

REPOSITORIES: biostudies-literature

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Publications

Cyclic AMP and calcium signaling are involved in antipsychotic-induced diabetogenic effects in isolated pancreatic β cells of CD1 mice.

Al-Ghafari Ayat A Elmorsy Ekramy Mahmoud EM Doghaither Huda Al HA Fahmy Eslam E

International journal of health sciences 20220901 5

<h4>Objectives</h4>Antipsychotics (APs) are medications used for different psychological disorders. They can introduce diabetogenic effects through different mechanisms, including cyclic adenosine monophosphate (cAMP) and calcium (Ca<sup>2+</sup>) signaling pathways. However, this effect is poorly understood. Therefore, this study aimed to evaluate the effect of three widely used APs (chlorpromazine, haloperidol, and clozapine) on cAMP and Ca<sup>2+</sup> signaling.<h4>Methods</h4>The local bioe ...[more]

PMID: 36101852

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Project description:1. The aim of this study was to determine the conditions under which the alpha2-adrenoceptor agonist UK14304 produces vasoconstriction in the porcine isolated ear artery. 2. UK14304 (0.3 microM) produced a small contraction of porcine isolated ear arteries which was 7.8+/-3.3% of the response to 60 mM KCl. Similar sized contractions were obtained after precontraction with either 30 nM angiotensin II, or 0.1 microM U46619 (8.2+/-1.8% and 10.2+/-2.6% of 60 mM KCl response, respectively). However, an enhanced alpha2-adrenoceptor response was uncovered if the tissue was precontracted with U46619, and relaxed back to baseline with 1-2 microM forskolin before the addition of UK14304 (46.9+/-9.6% of 60 mM KCl response). 3. The enhanced responses to UK14304 in the presence of U46619 and forskolin were not inhibited by the alpha1-adrenoceptor antagonist prazosin (0.1 microM), but were inhibited by the alpha2-adrenoceptor antagonist rauwolscine (1 microM), indicating that the enhanced responses were mediated via postjunctional alpha2-adrenoceptors. 4. In the presence of 0.1 microM U46619 and 1 mM isobutylmethylxanthine (IBMX), 1 microM forskolin produced an increase in [3H]-cyclic AMP levels in porcine isolated ear arteries. Addition of 0.3 microM UK14304 prevented this increase. 5. The enhanced UK14304 response was dependent upon the agent used to relax the tissue. After relaxation of ear arteries precontracted with 10 nM U46619 and relaxed with forskolin the UK14304 response was 46.9+/-9.6% of the 60 mM KCl response, and after relaxation with sodium nitroprusside (SNP) the response was 24.8+3.3%. However, after relaxation of the tissue with levcromakalim the UK14304 response was only 8.2+/-1.7%, which was not different from the control response in the same tissues (12.2+/-5.6%). An enhanced contraction was also obtained after relaxation of the tissue with the cyclic AMP analogue dibutyryl cyclic AMP (23.2+/-1.3%) indicating that at least part of the enhanced response to UK14304 is independent of the ability of the agonist to inhibit cyclic AMP production. 6. Relaxation of U46619 contracted ear arteries with SNP could be inhibited by the NO-sensitive guanylyl-cyclase inhibitor 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) indicating that production of cyclic GMP is necessary for the relaxant effect of SNP. However, ODQ had no effect on the relaxation of tissue by forskolin, suggesting that this compound does not act via production of cyclic GMP. Biochemical studies showed that while forskolin increases the levels of cyclic AMP in the tissues, SNP had no effect on the levels of this cyclic nucleotide. 7. In conclusion, enhanced contractions to the alpha2-adrenoceptor agonist UK14304 can be uncovered in porcine isolated ear arteries by precontracting the tissue with U46619, followed by relaxation back to baseline with forskolin, SNP or dibutyryl cyclic AMP before addition of UK14304. There was a greater contractile response to UK14304 after relaxation with forskolin than with SNP or dibutyryl cyclic AMP, suggesting that cyclic AMP-dependent and- independent mechanisms are involved in the enhancement of the UK14304 response.

Dataset Information

Cyclic AMP and calcium signaling are involved in antipsychotic-induced diabetogenic effects in isolated pancreatic β cells of CD1 mice.

Objectives

Methods

Results

Conclusion

Publications

Cyclic AMP and calcium signaling are involved in antipsychotic-induced diabetogenic effects in isolated pancreatic β cells of CD1 mice.

Similar Datasets

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