Faiz Ur Rahman1,2, Dae-Ryoung Park1,2, Yeonsoo Joe2,3, Kyu Yun Jang4, Hun Taeg Chung3, Uh-Hyun Kim1,2,5. 1. 1 Department of Biochemistry, Jeonju, Republic of Korea. 2. 2 National Creative Research Laboratory for Ca2+ Signaling Network, Chonbuk National University Medical School, Jeonju, Republic of Korea. 3. 3 Department of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea. 4. 4 Department of Pathology Chonbuk National University Medical School, Jeonju, Republic of Korea. 5. 5 Institute of Cardiovascular Research, Chonbuk National University Medical School, Jeonju, Republic of Korea.
Abstract
AIMS: Glucagon-like peptide-1 (GLP-1) increases intracellular Ca2+ concentrations, resulting in insulin secretion from pancreatic β-cells through the sequential production of Ca2+ mobilizing messengers nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR). We previously found that NAADP activates the neuronal type of nitric oxide (NO) synthase (nNOS), the product of which, NO, activates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which, in turn, induces cADPR formation. Our aim was to explore the relationship between Ca2+ signals and gasotransmitters formation in insulin secretion in β-cells upon GLP-1 stimulation. RESULTS: We show that NAADP-induced cGMP production by nNOS activation is dependent on carbon monoxide (CO) formation by heme oxygenase-2 (HO-2). Treatment with exogenous NO and CO amplifies cGMP formation, Ca2+ signal strength, and insulin secretion, whereas this signal is impeded when exposed to combined treatment with NO and CO. Furthermore, CO potentiates cGMP formation in a dose-dependent manner, but higher doses of CO inhibited cGMP formation. Our data with regard to zinc protoporphyrin, a HO inhibitor, and HO-2 knockdown, revealed that NO-induced cADPR formation and insulin secretion are dependent on HO-2. Consistent with this observation, the administration of NO or CO donors to type 2 diabetic mice improved glucose tolerance, but the same did not hold true when both were administered concurrently. INNOVATION: Our research reveals the role of two gas transmitters, CO and NO, for Ca2+ second messengers formation in pancreatic β-cells. CONCLUSION: These results demonstrate that CO, the downstream regulator of NO, plays a role in bridging the gap between the Ca2+ signaling messengers during insulin secretion in pancreatic β-cells.
AIMS: Glucagon-like peptide-1 (GLP-1) increases intracellular Ca2+ concentrations, resulting in insulin secretion from pancreatic β-cells through the sequential production of Ca2+ mobilizing messengers nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose (cADPR). We previously found that NAADP activates the neuronal type of nitric oxide (NO) synthase (nNOS), the product of which, NO, activates guanylyl cyclase to produce cyclic guanosine monophosphate (cGMP), which, in turn, induces cADPR formation. Our aim was to explore the relationship between Ca2+ signals and gasotransmitters formation in insulin secretion in β-cells upon GLP-1 stimulation. RESULTS: We show that NAADP-induced cGMP production by nNOS activation is dependent on carbon monoxide (CO) formation by heme oxygenase-2 (HO-2). Treatment with exogenous NO and CO amplifies cGMP formation, Ca2+ signal strength, and insulin secretion, whereas this signal is impeded when exposed to combined treatment with NO and CO. Furthermore, CO potentiates cGMP formation in a dose-dependent manner, but higher doses of CO inhibited cGMP formation. Our data with regard to zinc protoporphyrin, a HO inhibitor, and HO-2 knockdown, revealed that NO-induced cADPR formation and insulin secretion are dependent on HO-2. Consistent with this observation, the administration of NO or CO donors to type 2 diabeticmice improved glucose tolerance, but the same did not hold true when both were administered concurrently. INNOVATION: Our research reveals the role of two gas transmitters, CO and NO, for Ca2+ second messengers formation in pancreatic β-cells. CONCLUSION: These results demonstrate that CO, the downstream regulator of NO, plays a role in bridging the gap between the Ca2+ signaling messengers during insulin secretion in pancreatic β-cells.