Reduced vas deferens contraction and male infertility in mice lacking P2X(1) receptors

P2X(1) receptors for ATP are ligand-gated cation channels, present on many excitable cells including vas deferens smooth muscle cells(1-5). A substant ial component of the contractile response of the vas deferens to sympatheti c nerve stimulation, which propels sperm into the ejaculate. is mediated th rough P2X receptors'. Here we show that male fertility is reduced by simila r to 90% in mice with a targeted deletion of the P2X(1) receptor gene. Male mice copulate normally-reduced fertility results from a reduction of sperm in the ejaculate and not from sperm dysfunction. Female mice and heterozyg ote mice are unaffected. In P2X(1)-receptor-deficient mice, contraction of the vas deferens to sympathetic nerve stimulation is reduced by up to 60% a nd responses to P2X receptor agonists are abolished. These results show tha t P2X(1) receptors are essential for normal male reproductive function and suggest that the development of selective P2X(1) receptor antagonists may p rovide an effective non-hormonal male contraceptive pill. Also, agents that potentiate the actions of ATP at P2X(1) receptors may be useful in the tre atment of male infertility.