Role of NTPDase1 and extracellular nucleotides in smooth muscle cell contraction

NTPDase1和胞外核苷酸在平滑肌细胞收缩中的作用

• 批准号: RGPIN-2015-06580
• 负责人: Sévigny, Jean
• 金额: $ 2.48万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=591150
• 关键词: Role; NTPDase1; extracellular; nucleotides; smooth

Nucleotides (ATP, ADP, UTP and UDP) are released in a regulated manner by cells and tissues such as smooth muscle cells (SMC) and nerves innervating SMC. Once outside the cell, these molecules activate specific P2-receptors. The hydrolysis of ATP and ADP to adenosine by ectonucleotidases terminates the latter's effects and causes the activation of adenosine (or P1) receptors which often results in different physiological effects to those elicited by P2-receptor activation. We recently demonstrated that NTPDase1 was the dominant ectonucleotidase in vascular SMC and that mice deficient in NTPDase1 unmasked a major vasoconstrictor effect of nucleotides via P2Y6. More recently we observed that NTPDase1 was expressed in non-vascular SMC of the vas deferens and that its activity was necessary to prevent P2X1 functionality. The absence of NTPDase1 in vas deferens led to impaired peristalsis, reduced spermatozoa concentration in the semen, and reduced fertility. We therefore hypothesize that NTPDase1 is the major ectonucleotidase at the surface of SMC in all organs and that its presence affects contraction via the regulation of the P2 receptor agonist levels. We also hypothesize that NTPDase1 can limit the activation of some receptors while its presence may be necessary to prevent some other nucleotide receptors from desensitization. To evaluate our hypotheses, we have designed the following objectives.

核苷酸（ATP， ADP， UTP和UDP）由细胞和组织（如平滑肌细胞（SMC）和支配SMC的神经）以调节的方式释放。一旦离开细胞，这些分子就会激活特定的p2受体。外核苷酶将ATP和ADP水解为腺苷，终止后者的作用，并引起腺苷（或P1）受体的激活，这通常导致与p2受体激活不同的生理效应。我们最近证明了NTPDase1是血管SMC中主要的外核苷酸酶，并且NTPDase1缺乏的小鼠通过P2Y6揭示了核苷酸的主要血管收缩作用。最近，我们观察到ntppdase在输精管的非血管性SMC中表达，其活性对于阻止P2X1功能是必要的。输精管中ntpase的缺失导致精子蠕动受损，精液中精子浓度降低，生育能力降低。因此，我们假设ntpase是所有器官SMC表面的主要外核苷酶，其存在通过调节P2受体激动剂水平影响收缩。我们还假设NTPDase1可以限制一些受体的激活，而它的存在可能是防止一些其他核苷酸受体脱敏所必需的。为了评估我们的假设，我们设计了以下目标。