The T cell receptor ζ chain is required for efficient receptor expression and contributes to T cell receptor-mediated activation of ZAP-70 and PLC-γ1 as well as other signaling functions. A splice variant of ζ has been described which contains a 3bp insert coding for a glutamine in the cytoplasmic domain. The variant, here designated ζ-Q, is abundant, comprising 20-50% of ζ transcripts in humans, and production of the two isoforms is conserved among distantly related vertebrate species. Analysis of the peptide region in which the insert occurs reveals an unexpected homology with G-protein γ chains. Transfection studies suggest that disruption in the alignment of three conserved prolines by the insertion of an extra glutamine impairs TCR-mediated PLC activation. Experiments with human lymphocytes suggest that ζ-Q message undergoes upregulation following cellular activation. Our data suggest that regulation of the relative levels of these two transcripts is related to an ancient mechanism which functions to raise the number of receptors required to produce cellular activation during the course of prolonged cellular stimulation, perhaps through a G-protein-related pathway. © 2003 Elsevier Inc. All rights reserved.