MECHANISM FOR SIGNAL TRANSDUCTION OF OPIOID RECEPTOR STIMULATION OF MYOCYTES

阿片受体刺激心肌细胞的信号转导机制

• 批准号: 3789781
• 负责人: E LAKATTA
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3789781
• 关键词: biological signal transduction; calcium channel; calcium flux; calcium metabolism; enkephalins; heart cell; heart contraction; heart pharmacology; heart ventricle; laboratory rat; leucine; mature animal; myocardium; naloxone; neurotransmitter metabolism; opioid receptor; sarcolemma; sarcoplasmic reticulum; stimulant /agonist; voltage /patch clamp

The recent discovery of the presence of opioid peptide receptors on cardiac ventricular cells has prompted investigation of functional effects that result from stimulation of these receptors. In this regard, a naturally occurring opioid peptide, Leucine enkephalin (Leuenk), a delta receptor agonist, leads to a marked reduction in the twitch amplitude of single adult rat ventricular myocytes. This effect is due, in large part, to a reduction in the amplitude of the cytosolic Ca2+ transient (Cai). The Cai transient following the excitation of heart cells is due to activation of L-type sarcolemmal Ca2+ channels leading to Ca2+ influx via these channels (ICa). This Ca2+ influx triggers Ca2+ release from the sarcoplasm reticulum (SR) and also loads the SR with Ca2+ for subsequent releases. The specific mechanism by which Cai is reduced by Leuenk have been partly elucidated. Leuenk causes a release of Ca2+ from the SR and leads to a reduction in the amount of Ca2+ in the SR stores. These effects may be attributable to an increase in IP3 and IP4 produced by Leuenk. However, it is unknown whether Leuenk also decreases ICa. In this regard, the effect of opioid peptides to block neurotransmitters release from neurons has been attributed to a reduction in Ca2+ channel current in these cells. In the present study we determined the effect of Leuenk on ICa of individual cardiac ventricular cells freshly isolated from adult rats. ICa was measured via patch pipette in the whole cell voltage clamp mode. We observed that Leuenk (10-7M) decreases the amplitude of ICa by 40% during regular stimulation at 0.2 Hz at 23 degree C. Thus the ICa IV relation was not altered by Leuenk. The ICa depression by Leuenk was abolished by Naloxone, a specific k receptor antagonist. The ICa inactivation kinetics were unaffected by Leuenk. That Leuenk decreases the magnitude of ICa indicates that stimulation of delta opioid receptors leads to both a reduction in the magnitude of the trigger for Ca2+ release and to a reduction in Ca2+ loading of the SR. Thus, the opioid peptide effects to decrease the Cai transient and contraction amplitudes in individual cardiac ventricular cells, are, in part, due to a reduction in ICa.

最近发现了阿片肽受体的存在