Plasticity in KCNQ1 Subcellular Distribution and Partnership with Different KCNE Subunits Contribute to Variations in IKs Channel Function in the Heart

Abstract

Background: KCNQ1 can associate with KCNE1 - KCNE5 subunits, singly or in combination, and assume different channel phenotypes in current amplitude and gating kinetics. In the heart, KCNQ1 is known to partner with KCNE1 to form the slow delayed rectifier (IKs) channel, a major contributor to cardiac electrical heterogeneity and stabilizer of heart rhythm. It is unclear whether KCNQ1 can partner with other KCNE subunits expressed in the heart, and how these potential partnerships impact on IKs channel function. Methods: We study the above issues by patch clamping, immunoblotting, and immunofluorescence/confocal microscopy. Results: (1) IKs current density is higher in guinea pig (GP) atrial (A) than ventricular (V) myocytes. There are 2 contributing factors: KCNQ1 protein level is higher in A than in V, and KCNQ1 is colocalized with KCNE1 in the peripheral cell surface to a higher degree in A than in V. (2) IKs current density in V myocytes is much lower in spontaneously hypertensive rat (SHR) than in GP, despite abundant expression of KCNQ1 and KCNE1 in SHR. This coincides with a higher degree of KCNQ1 colocalization with KCNE2 in SHR than in GP V myocytes, and the current-suppressing effect of KCNE2 on IKs. (3) IKs is upregulated during aging in SHR V myocytes. This correlates with a modest increase in KCNQ1 protein expression and, importantly, a prominent redistribution of KCNQ1 and a higher degree of colocalization with KCNE1 on the peripheral cell surface. Conclusion: We propose that the KCNQ1 channel exhibits plastic subcellular distribution patterns and dynamic partnerships with KCNE1 and KCNE2 in the heart. These factors contribute to IKs channel remodeling in response to variations in work load or changes in the heart rate.