TMEM38A and TMEM38B are two recently identified trimeric intracellular cation (TRIC) channel subtypes. TMEM38A is preferentially expressed in excitable tissues such as striated muscle and brain and localizes to the sarcoplasmic reticulum (SR) in muscle tissues. Mice deficient in both TMEM38A and TMEM38B suffer embryonic cardiac failure; the cardiac myocytes display severe dysfunction in SR Ca2+ handling, weakened Ca2+ release, and reduced K+ permeability indicating that the TRIC cation channels are likely to act as counter-ion channels that function in synchronization with Ca2+ release from intracellular stores. Other experiments have shown that TMEM38A and TMEM38B can act with junctophilin proteins to support efficient ryanodine receptor-mediated Ca2+ release in muscle cells.