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Physiol. Genomics 13: 85-95, 2003. First published February 20, 2003; doi:10.1152/physiolgenomics.00057.2002
1094-8341/03 $5.00
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Received 9 May 2002; accepted in final form 19 February 2003.
Physiological Genomics 13:85-95 (2003)
1094-8341/03 $5.00 © 2003 American Physiological Society

A splice variant of the G protein ß3-subunit implicated in disease states does not modulate ion channels

Victor Ruiz-Velasco and Stephen R. Ikeda

Laboratory of Molecular Physiology, Guthrie Research Institute, Sayre, Pennsylvania 18840

A single-nucleotide polymorphism (C825T) in the GNB3 gene produces an alternative splice variant of the heterotrimeric G protein ß3 subunit (Gß3). Translation of the alternatively spliced mRNA results in a protein product, Gß3-s, in which 41 amino acids are deleted from Gß3. Interestingly, previous studies indicate that the C825T allele occurs with a high frequency in patients with certain vascular disorders. However, little information is available regarding the functional role Gß3-s might play in ion channel modulation. To examine this aspect, Gß3 or Gß3-s, along with either G{gamma}2 or G{gamma}5, were expressed in rat sympathetic neurons by nuclear microinjection of vector encoding the desired protein. In contrast to Gß3, expression of Gß3-s did not modulate N-type Ca2+ or G protein-gated inwardly rectifying K+ channels. In addition, Gß3-s did not appear to complex with a pertussis toxin-insensitive mutant of G{alpha}i2 or couple to natively expressed {alpha}2-adrenergic receptors. Finally, fluorescence resonance energy transfer (FRET) measurements indicated that enhanced yellow fluorescent protein (EYFP)-labeled Gß3-s does not form a Gß{gamma} heterodimer when coexpressed with enhanced cyan fluorescent protein (ECFP)-labeled G{gamma}2. Therefore, when expressed in sympathetic neurons, Gß3-s appears to lack biological activity-hence pathological conditions in patients carrying the homozygous C825T allele may result from a functional knockout of Gß3.

Gß3-s; signal transduction; ion channel modulation; FRET; N-type calcium channels




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Effects of the G protein {beta}3-subunit gene C825T polymorphism: should hypotheses regarding the molecular mechanisms underlying enhanced G protein activation be revised? Focus on "A splice variant of the G protein {beta}3-subunit implicated in disease states does not modulate ion channels"
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