A MINK-HERG COMPLEX REGULATES THE CARDIAC POTASSIUM CURRENT I-KR

MinK is a widely expressed protein of relative molecular mass similar to 15K that forms potassium channels by aggregation with other membran e proteins(1-3) MinK: governs :ion channel activiation(4) regulation b y second messengers(5,6), and the function and structure of the ion co nduction pathway(7,8). Association of minK with a channel protein know n as KvLQT1 produces a voltage-gated outward K+ current (I-sK) resembl ing the slow cardiac repolarization current (I-Ks)(9,10). HERG, a huma n homologue of the ether-a-go-go gene of the fruitfly Drosophila melan ogaster, encodes a protein that produces the rapidly activating cardia c delayed rectifier (I-Kr)(11,12). These two potassium currents, I-Kc, and I-Kr, provide the principal repolarizing currents in cardiac myoc ytes for the termination of action potentials(13,14). Although heterol ogously expressed HERG channels are largely indistinguishable from nat ive cardiac I-Kr, a role for minK in this current is suggested by the diminished I-Kr in an atrial tumour line subjected to minK antisense s uppression(15). Here we show that HERG and minK form a stable complex, and that this heteromultimerization regulates I-Kr activity. MinK, th rough the formation of heteromeric channel complexes, is thus central to the control of the heart rate and rhythm.