Interactions of HCN4 with LRMP and IRAG

The hyperpolarization-activated cyclic-nucleotide sensitive channel, HCN4, is critical for excitability of cardiac pacemaker cells. We recently identified two isoform-specific regulators of HCN4, lymphoid restricted membrane protein (LRMP, IRAG2) and inositol triphosphate receptor-associated guanylate-cyclase substrate (IRAG). LRMP and IRAG are ER-transmembrane proteins with cytoplasmic N-termini and coiled-coil domains. Interestingly these homologous proteins exhibit opposing effects on HCN4, with LRMP causing a loss-of-function by inhibiting the cAMP-dependent depolarizing shift in voltage-dependent activation, and IRAG causing a gain-of-function by inducing a depolarizing shift in voltage-dependence in the absence of cAMP.