Kv channels play a crucial role in determining the resting membrane potential, shaping action potential repolarization and setting spike frequency. It is becoming increasingly clear that the subcellular localization of these channels is an important component of cellular excitability. Very little is known about the localization of specific ion channels within cardiac myocytes. Kv2.1 is a delayed rectifier K+ channel expressed in both atria and ventricle, where it plays an important role in the late phase of repolarization of the cardiac action potential and helps set the QT interval. Kv2.1 is unusual among the voltage-gated K+ channels in that its function is modulated by hypoxia/ischemia, redox, mitochondria! Ca2+ and muscarinic agonists. It is intriguing that channel localization is also altered by these stimuli, suggesting a tight relationship between channel function and localization. In the brain, the altered function of Kv2.1 following ischemic insult appears to be neuroprotective. It is therefore likely that Kv2.1 plays a similar role in the heart, where the channel is differentially localized in atrial vs. ventricular myocytes. The hypothesis of this proposal is that the localization of Kv2.1 to subcellular microdomains places the channel in proximity to the signaling pathways that modulate its function in response to cellular stimuli, permitting dynamic regulation of cardiac excitability on a beat-tobeat basis. We have found that most of the Kv2.1 channels on the plasma membrane do not conduct K+, although they are still responsive to changes in membrane potential. Adenoviral-mediated expression of tagged channels will be used to study the localization and dynamics of Kv2.1 in living myocytes, thus building a foundation for the independent phase research. In the ROO phase, emphasis will be on investigating the role of Kv2.1, particularly these """"""""silent"""""""" channels, in the cardiac cellular response to ischemia and ntracellular Ca2+. We propose that the localization of Kv2.1 and consequently, channel function, will be altered by these stimuli.
Idiopathic arrhythmias and cardiac ischemia are serious threats to human health whose underlying causes are not well understood. Therefore, defects in ion channel localization may be an as-yet unrecognized cause of human cardiac disease, emphasizing the importance of understanding how these proteins are rafficked and localized in the heart.
| Baver, S B; O'Connell, K M S (2012) The C-terminus of neuronal Kv2.1 channels is required for channel localization and targeting but not for NMDA-receptor-mediated regulation of channel function. Neuroscience 217:56-66 |
| O'Connell, Kristen M S; Loftus, Robert; Tamkun, Michael M (2010) Localization-dependent activity of the Kv2.1 delayed-rectifier K+ channel. Proc Natl Acad Sci U S A 107:12351-6 |
