The Delayed Rectifier Channel Current I_K Plays a Key Role in the Control of Programmed Cell Death by PACAP and Ethanol in Cerebellar Granule Neurons

Abstract

Alcohol exposure during development causes severe brain malformations, and thus, identification of molecules that can counteract the neurotoxicity of ethanol deserves high priority. Since activation of potassium (K+) currents has been shown to play a critical role in the control of programmed cell death, we have investigated the effects of ethanol and PACAP on K+ currents in cultured cerebellar granule cells using the patch-clamp technique in the whole cell configuration. In the presence of the fast-inactivating IA current blocker 4-AP, a focal application of ethanol (200 mM) in the vicinity of granule cells provoked a robust hyperpolarization and a marked increase of the delayed rectifier IK current. Addition of PACAP (0.1 microM) in the bath solution prevented ethanol-induced membrane hyperpolarization and suppressed the stimulatory effect of ethanol on IK current. These data suggest that ethanol alters neuronal survival, at least in part, through activation of IK, and that PACAP abolishes ethanol-induced cerebellar granule cell death via inhibition of IK..

Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanisms of Fine Tuning of Brain Activity

“…NMDA receptor was also shown to be indirectly activated by PACAP (Llansola et al, 2004) or cAMP/PKA signaling (Costa et al, 2009). PAC1/PKA signaling controls cellular apoptosis through inhibition of potassium channels (Mei et al, 2004; Castel et al, 2006; Pugh and Margiotta, 2006) or induction of calcium channels (Pugh and Margiotta, 2006). PAC1/PKA-mediated activation of ion channels leads to activity-dependent neuronal differentiation and synaptic plasticity (Lee et al, 1999; Maturana et al, 2002; Grumolato et al, 2003; Nishimoto et al, 2007).…”

Voltage-Gated Potassium Channels at the Crossroads of Neuronal Function, Ischemic Tolerance, and Neurodegeneration

“…In contrast, lymphocytes cultured under hypotonic conditions undergo a 50% drop in K + concentrations via a volume regulatory response, but this reduction alone is not sufficient to induce apoptosis [24]. Similarly, serum deprivation along with decreased extracellular K + is required to stimulate apoptosis in CGNs, while in cortical neurons, caspase activity inhibition blocks oxidant-induced apoptotic cell death, despite the presence of prominent increased outward K + currents [45–49, 51, 64, 90, 91]. …”

“…For example, the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway has been implicated in K + channel-mediated apoptosis. In CGNs, cAMP-promoting agents reduce Kv channel-facilitated apoptosis induced by low extracellular K + or ethanol treatment [46, 48, 51, 66, 91]. In contrast, cAMP/PKA/CREB activation promotes the Kv2.1-mediated rise in K + currents and subsequent cell death in cholesterol-enhanced, low K + -mediated apoptosis [52].…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…11). The inhibitory effect of PACAP on potassium channels also contributes to the control of cell death (Zerr and Feltz, 1994;Mei et al, 2004;Castel et al, 2006). It has been proposed that activation by PACAP of the phosphatidylinositol 3Ј-OH kinase (PI3-K) neuroprotective pathway may synergize with the PKA cascade to promote cell survival (Fig.…”