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1.A.48 The Anion Channel Tweety (Tweety) Family

The Tweety family of anion channel proteins is present in animals and plants. These proteins contain about 500 - 1200 aas and 5 TMSs in an arrangement: 2 + 2 + 1, with an extra N-terminal TMS present in some plant homologues (e.g., NP_178935). They produce large conductance chloride (maxi-Cl-) currents. Calcium-activated chloride currents can be recorded in almost all cells. Tweety, a gene located in the Drosophila flightless locus, possesses five or six TMSs, and a human homologue of tweety (hTTYH3) is a large-conductance Ca2+-activated Cl- channel, while the related gene, hTTYH1, is a swelling-activated Cl- current. hTTYH3 is expressed in excitable tissues, including the heart, brain and skeletal muscle, whereas hTTYH1 is expressed mainly in the brain (Suzuki 2006).  The hTTYH3-induced Cl- current had a linear current-voltage relationship, a large single-channel conductance (260 pS) and the anion permeability sequence I- > Br- > Cl-. The hTTYH3 channel shows complex gating kinetics and voltage-dependent inactivation, dependent on a micromolar intracellular Ca2+ concentration.

'Tweety has three human homologues (hTTYH1-3) which are all maxi-Cl- channel proteins (Suzuki and Mizuno, 2004). He et al., (2008) provided evidence for a structure for Tweety family proteins which incorporates five membrane-spanning domains with a topology in which the N-terminus is located extracellularly and the C-terminus cytoplasmically. N-Glycosylation is important, but not essential, in the processing of members of the Tweety family. Incomplete N-glycosylation gives rise to reduced expression and increased ubiquitination (He et al., 2008).

hTTYH3 mRNA is distributes in excitable tissues. Positively charged amino acyl residues in the pore contribute to anion selectivity. The hTTYH3 single channel shows 26 picosiemen linear current voltage, complex kinetics and sensitivity to 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid.  This channel and hTTYH2 encode ionomycin-induced maxi-Cl- channels, but hTTYH1 encodes a Ca2+-independent, swelling-activated maxi-Cl- channel (Suzuki and Mizuno, 2004).

Homologues of Tweety are found in vertebrates, insects, worms and probably plants. They are prevalent in animals but scarce in plants. A search is in progress to identify homologues elsewhere.

References associated with 1.A.48 family:

He, Y., A.J. Ramsay, M.L. Hunt, A.K. Whitbread, S.A. Myers, and J.D. Hooper. (2008). N-glycosylation analysis of the human Tweety family of putative chloride ion channels supports a penta-spanning membrane arrangement: impact of N-glycosylation on cellular processing of Tweety homologue 2 (TTYH2). Biochem. J. 412: 45-55. 18260827
Suzuki, M. (2006). The Drosophila tweety family: molecular candidates for large-conductance Ca2+-activated Cl- channels. Exp Physiol 91: 141-147. 16219661
Suzuki, M. and A. Mizuno. (2004). A novel human Cl- channel family related to Drosophila flightless locus. J. Biol. Chem. 279: 22461-22468. 15010458