Four and a half LIM protein 1: a novel chaperone for atrium-specific Kv1.5 channels with a potential role in atrial arrhythmogenesis.

Chronic atrial diseases are associated with electrical, mechanical, and structural changes (remodelling) that result from activation of diverse signal transduction pathways. In atrial fibrillation (AF), the high atrial rate abbreviates the atrial action potential duration primarily by reduced ICa,L and increased inward-rectifier Kþ currents like the background current (IK1) and a constitutively active form of the acetylcholine-dependent Kþ current (IK,ACh). 1,2 There is also evidence for AF-associated reduction in the ultra-rapid delayed-rectifier IKur, although the reported findings have been inconsistent and the underlying molecular mechanisms are less clear. Response rate to antiarrhythmic drugs is low with respect to termination of AF or maintenance of sinus rhythm, and many of the drugs lead to adverse effects including ventricular arrhythmias. Given these limitations, an alternative approach is to design drugs that target atrium-selective ion channels like IKur, which plays a role in AF pathophysiology but not in ventricular function. However, our knowledge of the cellular processes underlying normal regulation of IKur are still incomplete. In order to contribute to atrial function in a specific way, the different ion channels have to be in the right place at the right time. This is regulated by multiple cellular processes, such as gene transcription, protein translation, trafficking, and membrane localization. Further fine-tuning is achieved by accessory channel subunits and by posttranslational protein modifications. Several findings have implicated accessory KChiP2 and Kvb1 subunits, and scaffold proteins like PDS97 and cytoskeletal a-actinin, in regulation of IKur or heterologously expressed K þ currents derived from the principal IKur channel a-subunit Kv1.5 (KCNA5). However, Kv1.5-based Kþ currents only partially reproduce the phenotype of native IKur, suggesting involvement of additional regulatory mechanisms. Yang et al. provide strong evidence that four and a half LIM protein 1 (FHL1) may represent a novel regulator of human atrial Kv1.5 channels. Specifically, using glutathioneS-transferase (GST) fusion protein and mass spectrometrybased techniques, the authors identified FHL1 as a potential protein partner of human Kv1.5 channels. LIM domain proteins like FHL1 recruit specific proteins, segregate these partners to discrete subcellular locations, and modulate their activities or assemble them into multi-protein complexes. Besides being involved in sarcomeric and signalling complexes in the cytosol, LIM domain proteins shuttle between the nucleus and cytosol and interact with transcription factors to regulate gene expression. There is emerging evidence that LIM domain proteins mediate the communication between the nuclear and plasma membrane compartments. Therefore, it is not surprising that Yang et al. found that FHL1 interacts with human Kv1.5 in the plasma membrane. These authors showed that FHL1 co-immunoprecipitates with Kv1.5 in both human atrium and in HEK293 and COS cells co-transfected with FHL1 and Kv1.5. In addition, immunolabelling of FHL1 and Kv1.5 confirmed their co-localization in the plasma membrane, further supporting potential physical interaction. Subsequent voltage-clamp experiments in COS cells showed that in the presence of FHL1 the amplitude of Kv1.5-derived Kþ current was approximately four-fold higher than in controls and that voltage-dependent activation was shifted to more positive potentials. FHL1 also increased the extent and accelerated the speed of slow inactivation and shifted its voltage-dependence to more positive potentials. Taken together, the FHL1-related current phenotype closely resembles that of IKur in atrial myocytes, 9 suggesting that FHL1 is a major regulator of atrial IKur. The results reported by Yang et al. raise several important issues that require further clarification. They do not provide evidence whether FHL1 itself or FHL1-targeted partners of Kv1.5 mediate the FHL1-associated alterations in Kv1.5 current. For instance, the LIM domain protein Enigma homlogue protein (ENH) acts as an adaptor protein for the formation of a functional protein kinase C1-ENH-N-type The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.