Grant: Project Grant

All signal processing depends on neurons correctly encoding input and transforming that into a series or pattern of spikes to convey the information to other cells in a circuit. We know that modulating the pattern of spike firing depends on calcium-dependent processes that create inhibitory feedback following spike discharge in the form of afterhyperpolarizations (AHPs). This process is so important that virtually every neuron generates a series of AHPs of increasing duration following a spike. In this way spike firing can be modulated over a timeframe of ~10 msec (fast AHP) to 10 sec (slow AHP). To understand how these responses are generated we need to identify the source of calcium increases and the calcium-gated potassium channels responsible for triggering the spike-AHP sequence. This study identifies a new level of interaction between calcium channels at the plasma membrane (PM) with an underlying cytoskeleton and even a deeper quilt-like membrane formed by the endoplasmic reticulum (ER). Our work builds on recent findings that the slow AHP arises from the concerted action of a voltage-gated calcium channel at the PM with ryanodine receptors that release calcium from the ER, which together activate a class of IK potassium channels. These interactions are enabled at "ER-PM" junctions where the ER extends narrow columns of membrane to within 10 nm of the PM. We propose that these sites in fact act as "CaRyK hubs" where multiple calcium sources and potassium channels are coassembled to reliably trigger an all-or-none spike-AHP sequence. Moreover, CaRyK hubs are distributed across the soma with a high degree of organization in the form of a polygonal (honeycomb-like) matrix we have traced to interactions with the cytoskeleton and even the underlying ER. The work is thus important in effectively identifying a new node of ion channel expression to mediate the calcium-dependent control of spike output necessary for neural coding and information transfer.