Date of Completion
hippocalcin, sAHP, PIP2, KCNQ
Field of Study
Physiology and Neurobiology
Doctor of Philosophy
The slow afterhyperpolarization (sAHP) is a post-spike, Ca2+-activated potassium conductance that limits neuronal excitability by responding to action potential-induced calcium signals. In addition to participating in learning and memory, the sAHP assumes an indispensable function underscored by its sensitivity to most neurotransmitters. Its absence, on the other hand, has been implicated in the pathophysiology of epilepsy and Alzheimer’s. Though the sAHP maintains a well-appreciated role in neurophysiology, its exact mechanism of activation remains unclear. Recent insights have emerged, however, providing us with new targets to explore in an effort to further understand sAHP physiology: (1) hippocalcin and other neuronal calcium sensor (NCS) proteins gate the calcium activation of the sAHP, (2) elevated membrane [PIP2] increases the sAHP’s calcium sensitivity, and (3) KCNQ channels as a candidate potassium channel family underlying sAHP currents.
Here, we test these key constituents of the sAHP machinery to shed light on the molecular mechanisms that control its unique properties. First, we find that the sAHP waveform is shaped by the actions of hippocalcin and its underlying channels. Next, we show that PIP2 is central to the sAHP process by examining the effect of PIPKIg on KCNQ channels. Our results indicate that PIPKIg catalyzes the [PIP2] necessary to allow KCNQ channels to function at subthreshold potentials typically observed during the sAHP time-course. Additionally, we show that muscarinic efficacy depends on hippocalcin, PIP2 affinity of KCNQ channels, and the timing of muscarinic receptor activation. Collectively, our data illustrate a collaboration between hippocalcin, type I PIP5Ks, and KCNQ channels towards shaping the sAHP response. Finally, we propose a model that likely resolves the sAHP activation mechanism that has remained elusive for over three decades.
Kim, Kwang S., "Molecular Mechanisms Regulating the Calcium-Activated Slow Afterhyperpolarization" (2016). Doctoral Dissertations. 1241.
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