A role for TREK1 in generating the slow afterhyperpolarization in developing starburst amacrine cells

Abstract

Slow afterhyperpolarizations (sAHPs) play an important role in establishing the firing pattern of neurons that in turn influence network activity. sAHPs are mediated by calcium-activated potassium channels. However, the molecular identity of these channels and the mechanism linking calcium entry to their activation are still unknown. Here we present several lines of evidence suggesting that the sAHPs in developing starburst amacrine cells (SACs) are mediated by two-pore potassium channels. First, we use whole cell and perforated patch voltage clamp recordings to characterize the sAHP conductance under different pharmacological conditions. We find that this conductance was calcium dependent, reversed at EK, blocked by barium, insensitive to apamin and TEA, and activated by arachidonic acid. In addition, pharmacological inhibition of calcium-activated phosphodiesterase reduced the sAHP. Second, we performed gene profiling on isolated SACs and found that they showed strong preferential expression of the two-pore channel gene kcnk2 that encodes TREK1. Third, we demonstrated that TREK1 knockout animals exhibited an altered frequency of retinal waves, a frequency that is set by the sAHPs in SACs. With these results, we propose a model in which depolarization-induced decreases in cAMP lead to disinhibition of the two-pore potassium channels and in which the kinetics of this biochemical pathway dictate the slow activation and deactivation of the sAHP conductance. Our model offers a novel pathway for the activation of a conductance that is physiologically important.

Expression and localisation of two-pore domain (K2P) background leak potassium ion channels in the mouse retina

“…To date only one study has confirmed a role for K2P channels in the retina. Ford et al 60,. have shown that TREK-1 contributes to slow after-hyperpolarisation events and regulates the frequency of retinal waves within starburst amacrine cells during early postnatal development.…”

Atoh1-dependent rhombic lip neurons are required for temporal delay between independent respiratory oscillators in embryonic mice

“…This same pattern of independent motor activity was also seen in respiratory output from internal intercostal muscles or VII motor roots, suggesting it is a general property of respiratory motor pools. Second, output from lumbar and thoracic roots (which innervate expiratory musculature) has previously been shown to require structures outside of the preBötC and the rostral ventral respiratory group, which are the well-established sources of rhythmic inspiratory drive and premotor innervation to the phrenic motor pool (Miller et al, 1985; Merrill and Lipski, 1987; Sasaki et al, 1991; Iscoe, 1998; Janczewski et al, 2002; de Almeida et al, 2010; Ford and Kirkwood, 2013). These anatomical differences are consistent with independent sources of respiratory drive to different motor pools serving inspiration and expiration, respectively, although we cannot rule out changes in connectivity during maturation (Iscoe, 1998).…”

In vivo treatment with the casein kinase 2 inhibitor 4,5,6,7‐tetrabromotriazole augments the slow afterhyperpolarizing potential and prevents acute epileptiform activity

“…This hyperpolarization is typically seen after repetitive action potential firing in most central nervous system (CNS) neurons and is mediated by a slowly inactivating K + outward current. Albeit the precise molecular nature of this conductance is yet unclear, there is evidence for involvement of SK‐type Ca 2+ ‐activated K + channels, KCNQ channels, HCN channels, and more recently even TREK1 channels—most probably depending on the cell type (Stocker et al., ; Stackman et al., ; Bildl et al., ; Yue & Yaari, ; Gu et al., ; Fernandez de Sevilla et al., ; Yue & Yaari, ; Gu et al, ; Tzingounis et al, ; Ford et al., ).…”

“…AHPs have been classically subdivided by temporal dynamics into fast (fAHP, 2–5 msec), medium (mAHP, 50–100 msec), and slow components (sAHP, 1–2 s; Storm, ). Although it is widely believed that K + outward currents underlie the AHP, the search for the molecular nature of distinct AHP classes (fAHP, mAHP, and sAHP) has revealed a number of K + channels including Ca 2+ ‐activated K + channels, KCNQ channels, hyperpolarization‐activated cyclic nucleotide gate nonselective (HCN) channels, and more recently even tandem pore weak inward rectifier K+ channel‐related K+ channel 1 (TREK1) channels (Stocker et al., ; Stackman et al., ; Bildl et al., ; Yue & Yaari, ; Gu et al., ; Fernandez de Sevilla et al., ; Yue & Yaari, ; Gu et al, ; Tzingounis et al, ; Ford et al., ). In particular, the molecular identity of the sAHP‐mediating K + channel appears to be largely cell‐type specific (see review by Andrade et al., ).…”