The Confluence of Population Genetics with Molecular Pharmacology at the Angiotensin II Receptor: Dawn of a New Era or Just a New Wrinkle?: Fig. 1.

Abstract

PubMed identifies 85,590 citations for the combined keyword set of angiotensin, angiotensinogen, renin, and angiotensin-converting enzyme, yet much remains to be elucidated about the mammalian angiotensin system(s) despite nearly 100 years of research (Bader et al., 2001). This reflects several facets of this small peptide autocoid. First, angiotensin II has been linked with a diverse set of functions essential for normal mammalian physiology and apparently contributes to a variety of clinical disorders. Second, multiple tissue angiotensin systems exist, each operating through different downstream mechanisms yet often resulting in the same end physiological effects. Third, this area of research has led to multiple billiondollar pharmaceuticals, and several of the original patents have or will soon expire, leading to efforts to find new proprietary materials. Fourth, it's a fun system to work with, because getting answers to experimental questions is not very difficult but interpreting and extrapolating the results becomes the main challenge. Last, but not least, genomic studies indicate that much of the interindividual variation in expression or functioning of this system, as well as response to system-directed pharmaceuticals, may reside in or be dictated by genetic variants (e.g., polymorphisms) (Baudin, 2002). It is this last facet that holds the promise for the future of angiotensin research and probably for all of pharmacology.Efforts to link the angiotensin system to human disorders, primarily hypertension, has been ongoing since the discovery of renin and angiotensin. We know of two human angiotensin II receptor subtypes, AT 1 and AT 2 , encoded by different genes, whereas rodents have two variants of the AT 1 subtype, AT 1A and AT 1B (Clauser et al., 1996). The majority of currently known actions of angiotensin are attributed to the AT 1 receptor, whereas functions of the AT 2 , apart from its actions in the central nervous systems and during development, remain somewhat controversial (Rosenstiel et al., 2002;Wagenaar et al., 2002). With the sequencing of angiotensin, pharmacologists and biochemists began to probe structure-function relationships of what is now known as the AT 1 subtype by synthesizing thousands of sequence variants of angiotensin II and measuring affinity, efficacy, and peptide conformation. Such studies led to the development of specific antagonists and identification of critical amino acid side chains necessary for potency and efficacy. Indirectly, they also provided the first views of receptor topography. These studies were soon complemented by measurements of AT 1 signal transduction pathways and all together established the AT 1 (and AT 2 ) as a classic G protein-coupled receptor. Cloning of the receptors opened the door to mutagenesis studies, and soon receptor amino acids were being attributed with receptor functions-ligand binding, internalization, signal transduction, etc. What was somewhat dismaying to investigators interested in function-disorder relationships was the finding...

Μελέτη Κλινικά Σημαντικών Γενετικών Πολυμορφισμών Του Ανθρώπινου Γονιδιώματος Σε Σχέση Με Παθήσεις Του Καρδιαγγειακού Συστήματος

“…υποδοχείς, οι τύπου 1 και 2, µε διαφορετική συγγένεια προς την AngII[151]. Η Ang-ΙΙ προσδένεται επιλεκτικά στην υψηλής συγγένειας περιοχή πρόσδεσης του AT1R, που βρίσκεται σε ποικίλους ιστούς, και ασκεί τη βιολογική της ενεργότητα, αυξάνοντας τον όγκο αίµατος και διατηρώντας τη φυσιολογική πίεση του αίµατος σε υποτασικές καταστάσεις[152].ου τους κωδικοποιούν εδράζονται σε διαφορετικά ρωµοσώµατα (ΑΤ1 στο χρωµόσωµα 3 και ΑΤ2 στο Χ χρωµόσωµα)[153].…”