Acetylcholine and ATP are excitatory cotransmitters in parasympathetic nerves. We used P2X 1 receptor antagonists to further characterize the purinergic component of neurotransmission in isolated detrusor muscle of guinea pig urinary bladder. In the presence of atropine (1 M) and prazosin (100 nM), pyridoxalphosphate-6-azophenyl-2Ј,4Ј-disulfonic acid (PPADS) (0.1-100 M) and suramin (1-300 M) inhibited contractions evoked by 4 Hz nerve stimulation in a concentration-dependent manner (IC 50 of 6.9 and 13.4 M, respectively). Maximum inhibition was 50 -60%, which was unaffected by coadministration of the ectonucleotidase inhibitor ARL67156
Abstract-The recent discoveries of inositol 1,4,5-trisphosphate (IP 3 ) receptor subtypes with different affinities for IP 3 and their potential involvement in development has important consequences for vascular smooth muscle. This study has examined the expression and distribution of the type 1 and type 3 IP 3 receptor subtypes in developing rat vascular smooth muscles. Immunoblotting of portal vein and aorta from neonatal (2 to 4 days) and fully developed (6 weeks) rats revealed significantly higher levels of the type 3 IP 3 receptor expression in neonatal, compared with developed, vascular smooth muscles. concentration. 1 It is now well established that a major pathway for increasing intracellular Ca 2ϩ in smooth muscle is the activation of phospholipase C via activation of a plasma membrane receptor, which leads to the production of inositol 1,4,5-trisphosphate (IP 3 ). 2 IP 3 binds to specific IP 3 receptors in the smooth muscle cell, which produces a release of Ca 2ϩ from the intracellular stores. 3,4 Several investigators have isolated full-length cDNA clones that encode at least 3 distinct IP 3 receptors: type 1, 5 type 2, 6 and type 3. 7,8 Type 1 IP 3 receptor is expressed in many cell types, 9 type 2 IP 3 receptor is expressed in brain and heart, 10 and type 3 IP 3 receptor is expressed predominantly in nonneural tissues. 7 Messenger RNA for type 1, 2, and 3 IP 3 receptors has been detected in nonvascular smooth muscle, 11,12 and in a vascular smooth muscle cell line, only mRNA for type 1 and type 3 receptors was detected. 13 In smooth muscle, the type 1 IP 3 receptor has been localized to the sarcoplasmic reticulum throughout the cell. 14 The role of the different IP 3 receptor subtypes in smooth muscle remains to be established, although distinct functions of the type 1 and type 3 IP 3 receptors are suggested by their different binding affinities for IP 3 ; type 3 receptor has a 10-fold lower affinity than type 1 receptor. 12 In vascular smooth muscle cells, alterations in the IP 3 receptor subtype expression and/or localization could have functional implications for Ca 2ϩ homeostasis in blood vessels. To date, no studies have investigated the IP 3 receptor subtypes expressed in vascular smooth muscle or examined possible circumstances in which these may be altered. There is evidence that the expression of IP 3 receptor subtypes changes during differentiation in some cell types, which suggests a possible involvement in cell development. 15,16 Developmentally associated alterations in messenger RNA levels for IP 3 receptors have also been observed in the mouse cerebellum. 17 These developmental changes may occur in vascular smooth muscle, which given the difference in IP 3 affinities of the different subtypes, 12 could potentially have functional implications for the regulation of blood vessel development.This study examined the expression and distribution of the type 1 and type 3 IP 3 receptor in vascular smooth muscle from neonatal and fully developed rats. We reveal a significant
Osteoporosis is a multifactorial disease with a strong genetic component characterized by reduced bone density and increased fracture risk. A candidate locus for regulation of hip bone mineral density (BMD) has been identified on chromosome 1p36 by linkage analysis. One of the positional and functional candidate genes located within this region is the tumour necrosis factor receptor superfamily member 1B (TNFRSF1B). In order to investigate whether allelic variation in TNFRSF1B contributes to regulation of bone mass, we studied several polymorphisms of this gene in a population based cohort study of 1240 perimenopausal women from the UK. We studied a T676G change in exon 6 (196: Met-Arg) and three SNPs (G593A, T598G, and T620C) in the 3'UTR of the gene. The 3'UTR SNPs were in strong linkage disequilibrium (LD) with each other (P<0.00001), and the exon 6 SNP was in LD with G593A and T598G (P<0.00001). We found no association between T676G alleles and BMD at the spine or hip. However, haplotype analysis showed that subjects homozygous for the A593-T598-C620 haplotype (n=85) had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (n=1155; P<0.00008) and this remained significant after correcting for confounding factors and multiple testing (P<0.0009). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight. In summary, our work supports the view that allelic variation in the 3'UTR of TNFRSF1B gene contributes to the genetic regulation of bone mass, with effects that are specific for femoral neck BMD.
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