A Molecular and Pharmacological Study of the α1- Adregenergic Receptors: From the Novel Alternatively Spliced α1A-AR Isoforms to the Acute Effects of the Triiodothyronine
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Authors
Dang, Herbert
Issue Date
2002-12-06
Volume
Issue
Type
Dissertation
Language
en_US
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Abstract
Numerous literary works dating as far back as the turn of the 19th century contain precise physiological descriptions of adrenergic stimulatory effects on the human body, which offer testimony to our interest in adrenergic receptors or adrenoceptors. In fact the earliest recorded documentation alluding to the existence of adrenoceptors dates to the 1905, where it was observed that the increase in blood pressure by adrenaline could be reversed by ergotoxine. It was not until the late 1940’s, when the adrenoceptors were classified into (X and ß types, that our trivial fascination with these receptors was transformed into a euphoria of scientific investigations. As a result, our exploration into the adrenoceptors has tremendously enlightened our pharmacological insights and drug perceptions. Such things as the physical structure, the biological function, the production of second messenger chemicals, the synthesis and degradation, and even the regulation of the adrenoceptors have been uncovered by scientific inquiry. This accumulating data on the adrenoceptors has not only rewardedmankind with a multitude of therapeutic applications for many diseases and disorders, but has brought to the forefront the preeminent role the adrenergic system plays in the human body. Today, agonists and antagonists of adrenoceptors are used to treat a wide range of ailments, from cardiovascular diseases like hypertension, to asthma and nasal sinus congestion.
To date, there are two major categories of adrenoceptors recognized, the a and ß adrenergic receptors (-AR). The a-ARs generally are associated with constriction of blood vessels, while the ß-ARs with vasodilatation. The a-AR is further divided into the two subgroups: the arAR and the a2-AR. The study of the a,-AR is of particular importance for the cardiovascular system and secretory glands, and therefore is the chief focus of our scientific investigation. With this in mind, the first series of projects dealt with the examination of the distribution of mRNA transcripts for each of the a,-AR subtypes (a1A-AR, a1B-AR, and a1D-AR ) using the sensitive molecular technique of competitive reverse transcription- polymerase chain reaction (RT-PCR). Initially, I investigated the transcripts present in the various cells that comprise the rat parotid, and then characterized the transcripts in assorted tissues of the rat heart.
The overall goal of my first project was to document quantitative differences among the three arAR mRNA levels among the tissues, which would
perchance indicate functional diversity. In the first study, I found that the a1D- AR subtype mRNA transcript was present in the acinar cells, but was undetectable in the duct cells. The second study involved the detection and quantification of the three 01,-AR subtypes amid the various tissues and cells that compose the heart, such as between the ventricle and atrium. I found that the three a,-AR subtypes are discretely distributed throughout the heart. The a1B- AR subtype mRNA transcripts was by far the most expressed, with the left ventricle having the highest levels.
Of the three acknowledged (X,-ARs subtypes, the remainder of this dissertation primarily focuses on the transcript variants of the oc1A-AR. Over the past few years, production of these variants by alternative splicing has been of particular importance to geneticists. With almost all of the human genome sequenced, scientists are perplexed by the gross underestimation of genes. It is now believed that humans have far fewer genes than expected, at around 30,000- 35,000, as opposed to the initial 100,000’s prediction. When compaired with other species, the nematode worm has 18,000 while the fruit fly has around 13,000 genes. Therefore, in order to resolve this dilemma of having so few genes and so many proteins, the concept of alternative splicing emerged as a possible explanation. In its most basic element, alternative splicing allows the production of numerous proteins from one single gene.
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Creighton University
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Copyright is retained by the Author.
A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.
Copyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.