8.A.140. The Lymphoid-restricted Membrane Protein (LRMP) Family Ion channels in excitable cells function in macromolecular complexes in which auxiliary proteins modulate the biophysical properties of the pore-forming subunits. Hyperpolarization-activated, cyclic nucleotide-sensitive HCN4 channels are critical determinants of membrane excitability in cells throughout the body, including thalamocortical neurons and cardiac pacemaker cells (see TC#s 1.A.1.5.10 and 11). Peters et al. 2020 showed that the properties of HCN4 channels differ dramatically in different cell types, possibly due to endogenous expression of auxiliary proteins. They reported the discovery of a family of ER transmembrane proteins that associate with and modulate HCN4. The lymphoid-restricted membrane protein (LRMP, Jaw1) and inositol trisphosphate receptor-associated guanylate kinase substrate (IRAG, Mrvi1, and Jaw1L) are homologous proteins with small ER luminal domains and large cytoplasmic domains. Despite their homology, LRMP and IRAG have distinct effects on HCN4. LRMP is a loss-of-function modulator that inhibits the canonical depolarizing shift in the voltage-dependence of HCN4 in response to the binding of cAMP. In contrast, IRAG causes a gain of HCN4 function by depolarizing the basal voltage dependence in the absence of cAMP. The mechanisms of action of LRMP and IRAG are independent of trafficking and cAMP binding, and they are specific to the HCN4 isoform. IRAG is highly expressed in the mouse sinoatrial node where computer modeling predicts that its presence increases HCN4 current. Thus, important roles for LRMP and IRAG in the regulation of cellular excitability are proposed (Peters et al. 2020).
References:
Beijer, D., M.F. Dohrn, A. Rebelo, M.C. Danzi, B.R. Grosz, M. Ellis, K.R. Kumar, S. Vucic, H. Vais, J.S. Weissenrieder, O. Lunko, U. Paudel, L.C. Simpson, V. Camarena, J. Raposo, M. Saporta, Y. Arcia, I. Xu, S. Feely, C.J. Record, J. Blake, M.M. Reilly, S.S. Scherer, M. Kennerson, Y.C. Lee, J.K. Foskett, M.E. Shy, and S. Zuchner. (2025). A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity. Brain 148: 227-237.
Peters, C.H., M.E. Myers, J. Juchno, C. Haimbaugh, H. Bichraoui, Y. Du, J.R. Bankston, L.A. Walker, and C. Proenza. (2020). Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins. Proc. Natl. Acad. Sci. USA 117: 18079-18090.
Examples:
TC#	Name	Organismal Type	Example
8.A.140.1.1	Inositol 1,4,5-triphosphate receptor associated 2, IRAG2, JAW1, LRMP, of 555 aas and one C-terminal TMS. It plays a role in the delivery of peptides to major histocompatibility complex (MHC) class I molecules which occurs in a transporter associated with antigen processing (TAP)-independent manner. It may also play a role in taste signal transduction via ITPR3 as well as during fertilization in pronucleus congression and fusion. It regulates HCN4 channels (Peters et al. 2020). A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth disease with variable severity (Beijer et al. 2025).		HCN4 channel regulator, IRAG2 of Homo sapiens

8.A.140.1.2	Uncharacterized protein of 959 aas and 2 TMSs, one about one-fourth from the N-terminus and one at the C-terminus.		*UP of Pygoscelis adeliae* (Adelie penguin)**

8.A.140.1.3	Lymphoid-restricted membrane protein-like, LRMP-L, isoform X1 of 1370 aas and one C-terminal TMS.		LRMP-L of Dendronephthya gigantea

8.A.140.1.4	Uncharacterized protein of 706 aas and one C-terminal TMS.		*UP of Hydra vulgaris* (swiftwater hydra)**

Examples:
TC#	Name	Organismal Type	Example
8.A.140.2.1	Uncharacterized protein of 475 aas and one C-terminal TMS [Penaeus vannamei		UP of Penaeus vannamei

8.A.140.2.2	Uncharacterized protein of 706 aas and 1 TMS, about one-third from the C-terminus.		*UP of Lamprigera yunnana* (firefly)**