Role of NTPDase1 and extracellular nucleotides in smooth muscle cell contraction

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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.