The expression of desensitization of myocardial beta-adrenoceptor signal transduction system

β-肾上腺素能受体转导系统的生化改变，是衰竭心脏或老化心脏心肌对儿茶酚胺反应减弱的基础，目前尚不清楚。最近，随着第一个哺乳动物腺酰环化酶的克隆，6个全长的哺乳动物腺酰环化酶亚型和2个其他腺酰环化酶的部分克隆已被报道。1)我们制备了5种不同的多克隆抗体，这些抗体的平均滴度约为10-3。此外，野百合碱(MCT)诱导的右室肥厚和衰竭心肌细胞膜上腺酰环化酶蛋白免疫印迹显示多条带。虽然这些多克隆抗体识别了一条110 kDa的条带，但我们不能检测到严格的组织特异性。2)我们研究了MCT诱导的右…大鼠心肌V型和VI型腺酰环化酶基因表达水平及其活性的变化更多的心脏肥厚和衰竭。这些数据表明，V和VI型腺酰环化酶稳态mRNA水平的降低与衰竭心室中腺酰环化酶催化亚单位本身的活性降低是平行的。然而，在没有衰竭的早期肥厚的心室中，腺酰环化酶的催化活性可能受到其他机制的调节，而不是它的基因表达。3)我们通过检测腺酰环化酶在胎鼠、新生大鼠、成年大鼠和成年大鼠心肌细胞膜上的腺酰环化酶途径的表达水平，研究了β-肾上腺素能受体-腺酰环化酶途径的发育调节及其各自的稳态mRNA水平的贡献。与年龄相关的心肌β-肾上腺素能受体转导系统活性的变化受β-肾上腺素能受体密度和腺苷环化酶催化活性的调节。具体地说，VI型腺酰环化酶异构体含量的减少是催化活性随年龄下降的基础。较少

Biochemical alteration in the beta-adrenoceptor transduction system, which underlie the diminishing response of the myocardium to catecholamines in failing hearts or aging heart, remains to be clarified. Recently, following the cloning of the first mammalian adenylyl cyclase, six full-length mammalian adenylyl cyclase isoforms and two partial clonings of other adenylyl cyclase have been reported.1) We produced five different polyclonal antibodies against the partial sequence of adenylyl cyclase V of VI.However, the average titer of these antibodies was about 10-3. In addition, western blots of adenylyl cyclase from myocardial membranes in monocrotaline (MCT)-induced right ventricular hypertrophy and failure showed multiple bands. Although we recognized a band of 110kDa by these polyclonal antibodies, we could not detect strict tissue specificity.2) We studied the alterations in myocardial mRNA levels of type V and VI adenylyl cyclase and its activity in rat heart with MCT-induced right … More ventricular hypertrophy and failure. These data suggested that a decrease in the steady state mRNA levels of type V and VI adenylyl cyclase paralleled with the impaired activity of the adenylyl cyclase catalytic subunit itself in the failing ventricle. However, adenylyl cyclase catalytic activity in the state of early hpertrophied ventricle without failure may be modulated by other mechanisms rather than its gene expression.3) We investigated the developmental regulation fo beta-adrenoceptor-adenylyl cyclase pathway in myocardial membranes form fetal, neonatal, adults and mature adult rats by measuring the adenylyl cyclase enzyme, and the contribution of the respective steady-state mRNA levels. The age-related changes in the activity of the myocardial beta-adrenoceptor transduction system are regulated by the density of beta-adrenergic receptors and by the activity of the catalyst adenylyl cyclase. In particular, a decrease in the content of the type VI isoform of adenylyl cyclase underlies the pattern of decreasing catalytic activity with age. Less