Progress toward elucidating the function of alpha1B-adrenergic receptors (alpha1BARs) in the central nervous system has been constrained by a lack of agonists and antagonists with adequate alpha1B-specificity. We have obviated this constraint by generating transgenic mice engineered to overexpress either wild-type or constitutively active alpha1BARs in tissues that normally express the receptor, including the brain. All transgenic lines showed granulovacular neurodegeneration, beginning in alpha1B-expressing domains of the brain and progressing with age to encompass all areas. The degeneration was apoptotic and did not occur in non-transgenic mice. Correspondingly, transgenic mice showed an age-progressive hindlimb disorder that was parkinsonian-like, as demonstrated by rescue of the dysfunction by 3, 4-dihydroxyphenylalanine and considerable dopaminergic-neuronal degeneration in the substantia nigra. Transgenic mice also had a grand mal seizure disorder accompanied by a corresponding dysplasia and neurodegeneration of the cerebral cortex. Both behavioral phenotypes (locomotor impairment and seizure) could be partially rescued with the alpha1AR antagonist terazosin, indicating that alpha1AR signaling participated directly in the pathology. Our results indicate that overstimulation of alpha1BAR leads to apoptotic neurodegeneration with a corresponding multiple system atrophy indicative of Shy-Drager syndrome, a disease whose etiology is unknown.

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␣ 1 -Adrenergic receptors (␣ 1A , ␣ 1B , and ␣ 1D ) are regulators of systemic arterial blood pressure and blood flow. Whereas vasoconstrictory action of the ␣ 1A and ␣ 1D subtypes is thought to be mainly responsible for this activity, the role of the ␣ 1B -adrenergic receptor (␣ 1B AR) in this process is controversial. We have generated transgenic mice that overexpress either wild type or constitutively active ␣ 1B ARs. Transgenic expression was under the control of the isogenic promoter, thus assuring appropriate developmental and tissue-specific expression. Cardiovascular phenotypes displayed by transgenic mice included myocardial hypertrophy and hypotension. Indicative of cardiac hypertrophy, transgenic mice displayed an increased heart to body weight ratio, which was confirmed by the echocardiographic finding of an increased thickness of the interventricular septum and posterior wall. Functional deficits included an increased isovolumetric relaxation time, a decreased heart rate, and cardiac output. Transgenic mice were hypotensive and exhibited a decreased pressor response. Vasoconstrictory regulation by ␣ 1B AR was absent as shown by the lack of phenylephrine-induced contractile differences between ex vivo mesenteric artery preparations. Plasma epinephrine, norepinephrine, and cortisol levels were also reduced in transgenic mice, suggesting a loss of sympathetic nerve activity. Reduced catecholamine levels together with basal hypotension, bradycardia, reproductive problems, and weight loss suggest autonomic failure, a phenotype that is consistent with the multiple system atrophy-like neurodegeneration that has been reported previously in these mice. These results also suggest that this receptor subtype is not involved in the classic vasoconstrictory action of ␣ 1 ARs that is important in systemic regulation of blood pressure.The adrenergic receptor family, which includes 3 ␣ 1 , 3 ␣ 2 , and 3 ␤-receptor subtypes, is a group of heptahelical G proteincoupled receptors that mediate the effects of the sympathetic nervous system. Extensive effort has been spent in classifying the three known ␣ 1 -adrenergic receptor (␣ 1 AR) 1 subtypes (␣ 1A , ␣ 1B , and ␣ 1D ) via molecular cloning techniques (1-4) and pharmacological analyses (5). The most well characterized cardiovascular regulatory actions associated with ␣ 1 AR activation include the contraction, growth and proliferation of vascular smooth muscle cells (6 -9), increased cardiac contractility (10), and regulation of the hypertrophic program in the myocardium (11,12). In other ␣ 1 AR-expressing tissues such as liver and kidney, the function of these receptors is to regulate metabolic processes (13) and sodium and water reabsorption (14), respectively. These responses are transduced primarily via receptor coupling to the G q /phospholipase C pathway (5), which leads to the subsequent activation of downstream signaling molecules including protein kinase C and inositol 1,4,5-trisphosphate.The progress toward elucidating the distinct regulatory role of each ␣ 1...

These data demonstrate that alpha1A-ARs protect the heart from ischemic injury through a staurosporine-sensitive signaling pathway that is independent of protein kinase C.