We used Xenopus oocytes co-expressing thyrotropin-releasing hormone (TRH) receptors and human ether-a-go-go-related gene (HERG) K+ channel variants carrying different amino-terminal modifications to check the relevance of the proximal domain for hormonal regulation of the channel. Deletion of the whole proximal domain (Delta 138-373) eliminates TRH-induced modifications in activation and deactivation parameters. TRH effects on activation are also suppressed with channels lacking the second half of the proximal domain or only residues 326-373. However, normal responses to TRH are obtained with Delta 346-373 channels. Thus, whereas residues 326-345 are required for the hormonal modulation of HERG activation, different proximal domain sequences contribute to set HERG gating characteristics and its regulation by TRH.