Role of NTPDase1 and Extracellular Nucleotides in Smooth Muscle Cell Contraction

本实验室的研究旨在阐明细胞外核苷酸信号的作用，并确定其在哺乳动物细胞中的作用模式。诸如ATP和ADP的核苷酸由诸如平滑肌细胞（SMC）和支配SMC的神经的细胞以调节的方式释放。一旦在细胞外，这些分子激活特定的P2受体。ATP和ADP通过外核苷酸酶水解为腺苷终止后者的作用并引起腺苷（P1）受体的激活，这通常导致与P2受体激活引起的生理效应不同的生理效应。我们最近证明，NTPDase1是占主导地位的外核苷酸酶在血管平滑肌细胞和小鼠NTPDase1缺陷揭示了一个主要的血管收缩作用的核苷酸通过P2Y6。最近，我们观察到NTPDase1在输精管的非血管SMC中表达，并且其活性对于阻止P2X1功能是必要的。输精管中缺乏NTPD酶1导致精子增殖受损，精液中精子浓度降低，生育力降低。因此，我们假设NTPDase1是一般非血管SMC表面的主要外核苷酸酶，其活性通过调节P2受体激动剂水平影响收缩。本研究计划的长期目标是阐明细胞外核苷酸信号在非血管平滑肌（SM）收缩中的作用和机制。为了解决这个问题，我们制定了以下目标。

The research of my laboratory aims to elucidate the roles of extracellular nucleotide signaling and to define their mode of action in mammalian cells. Nucleotides such as ATP and ADP are released in a regulated manner by cells 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 (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 non-vascular SMC in general and that its activity affects contraction via the regulation of the P2 receptor agonist levels. The long term objective of this research program is to elucidate the role and mechanisms of extracellular nucleotide signaling in non-vascular smooth muscle (SM) contraction. To address this problem, we have designed the following objectives.