8.A.125. The Cleft Lip and Palate Transmembrane Protein 1 (Clptm1) Family GABAAR-associated proteins include the Cleft lip and palate transmembrane protein 1 (Clptm1) which interacts with all GABAAR subunits and promotes GABAAR trapping in the endoplasmic reticulum (Ge et al. 2018). Overexpression of Clptm1 reduces GABAAR-mediated currents in cultured hippocampal neurons and in brain with no effect on glycine or AMPA receptor-mediated currents. Conversely, knockdown of Clptm1 increased phasic and tonic inhibitory transmission with no effect on excitatory synaptic transmission. Furthermore, altering the expression level of Clptm1 mimicked activity-induced inhibitory synaptic scaling. Thus, in complement to other GABAAR-associated proteins that promote receptor surface expression, Clptm1 limits GABAAR forward trafficking and regulates inhibitory homeostatic plasticity (Ge et al. 2018).
References:
Ge, Y., Y. Kang, R.M. Cassidy, K.M. Moon, R. Lewis, R.O.L. Wong, L.J. Foster, and A.M. Craig. (2018). Clptm1 Limits Forward Trafficking of GABA Receptors to Scale Inhibitory Synaptic Strength. Neuron. 97: 596-610.e8.
Wang, Y., A.K. Menon, Y. Maki, Y.S. Liu, Y. Iwasaki, M. Fujita, P.A. Guerrero, D.V. Silva, P.H. Seeberger, Y. Murakami, and T. Kinoshita. (2022). Genome-wide CRISPR screen reveals CLPTM1L as a lipid scramblase required for efficient glycosylphosphatidylinositol biosynthesis. Proc. Natl. Acad. Sci. USA 119: e2115083119.
Yamamoto, K., A. Okamoto, S. Isonishi, K. Ochiai, and Y. Ohtake. (2001). A novel gene, CRR9, which was up-regulated in CDDP-resistant ovarian tumor cell line, was associated with apoptosis. Biochem. Biophys. Res. Commun. 280: 1148-1154.
Examples:
TC#	Name	Organismal Type	Example
8.A.125.1.1	*Clptm1 of 669 aas and 9 - 11 TMSs. Plays a direct role in trafficking and activity of the GABAA receptor (TC 1.A.9.5.2) by binding to it (Ge et al.* 2018)**		Clptm1 of Homo sapiens

8.A.125.1.2	ClptM1-like protein of 745 aas and 9 - 11 TMSs.		Clptm1 of Plasmodium gonderi

8.A.125.1.3	Clptm1 of 593 aas and 9 - 11 TMSs.		*Clptm1 of Arabidopsis thaliana* (Mouse-ear cress)**

8.A.125.1.4	ClpM1 of 657 aas and ~ 9 TMSs.		ClpM1 of Neurospora crassa

8.A.125.1.5	Cleft lip and palate transmembrane protein 1-like protein, Clptm1L, of 538 aas and possibly 7 TMSs in a 1 (N-terminal) + 3 + 3 TMS arrangement. It enhances cisplatin-mediated apoptosis, when overexpressed (Yamamoto et al. 2001). It is a lipid scramblase, required for efficient glycosylphosphatidylinositol biosynthesis (Wang et al. 2022). Scramblases translocate lipids across the lipid bilayer without consumption of ATP, thereby regulating lipid distributions in cellular membranes. Cytosol-to-lumen translocation across the endoplasmic reticulum (ER) membrane is a common process among lipid glycoconjugates involved in posttranslational protein modifications in eukaryotes. These translocations are thought to be mediated by specific ER-resident scramblases. Wang et al. 2022 showed that CLPTM1L, an integral membrane protein with seven or eight putative TMSs, is the major lipid scramblase involved in efficient glycosylphosphatidylinositol biosynthesis in the ER membrane. These results validate the long-standing hypothesis that lipid scramblases ensure the efficient translocations of lipid glycoconjugates across the ER membrane for protein glycosylation pathways.		CLPTM1L of Homo sapiens