Newly uncovered Cryo-EM structures of mammalian NCXs set a new stage for resolving the underlying molecular mechanisms and drug discovery.

The membrane-abundant NCX proteins mediate an electrogenic ion exchange (3Na+ :1Ca2+ ) in the Ca2+ -exit or Ca2+ -entry mode. The structurally related isoform/splice variants of NCX are expressed in a tissue-specific manner to shape Ca2+ signalling/homeostasis in diverse cell types. The lack of mammalian NCX structure hampered the functional and regulatory resolution of tissue-specific NCX variants and their pharmacological targeting. Recently unveiled Cryo-EM structures of human cardiac NCX1.1[1] and kidney NCX1.3[2] provide new opportunities for resolving structure/functional divergences among NCX variants and their pharmacological targeting.