Slowly Inactivating Potassium Conductance (ID): A Potential Target for Stroke Therapy

Abstract

Background and Purpose-Excessive accumulation of extracellular glutamate results in the death of most, but not all, neurons in the central nervous system. Understanding the unique properties of cells that can withstand this excitotoxic challenge may identify specific targets for novel stroke therapies. Methods-A combination of in vivo methods for analysis of excitotoxic cell death after activation of N-methyl-D-aspartate (NMDA) receptors and in vitro patch-clamp analysis of specific conductances in hypothalamic slices and dissociated cells has been used to assess the roles of specific potassium conductances in delayed cell death after NMDA receptor activation. Results-We report that a specific D-type potassium conductance (I D ), necessary for the rapid repolarization of the membrane after a strong depolarization, serves such a protective purpose in magnocellular neurons of the paraventricular nucleus. Manipulations that inhibit this current (4-aminopyridine or angiotensin II) increase neuronal excitability and augment cell death after NMDA receptor activation. In addition, this protection is not observed in magnocellular neurons of spontaneously hypertensive rats, and intriguingly it can be reestablished by blocking angiotensin II receptors in these animals. Conclusions-These observations provide a persuasive experimental explanation for the unexpected finding that therapeutic treatments for hypertension that block central as well as peripheral angiotensin type 1 receptors reduce the severity and occurrence of stroke.

ANG II-induced excitation of paraventricular nucleus magnocellular neurons: a role for glutamate interneurons

“…I A was further assessed by measuring the delay to first spike during a depolarizing current pulse from a hyperpolarized membrane potential. Such measurements also indicated ANGinduced reduction in I A with a decrease in the time to first spike being observed as reported previously from our laboratory (1). These data are in agreement with previous voltage-clamp experiments showing ANG effects on I A in magnocellular neurons in PVN (26) and supraoptic nucleus (SON) (30).…”

Vasopressin Differentially Modulates Non-NMDA Receptors in Vasopressin and Oxytocin Neurons in the Supraoptic Nucleus

“…It is interesting that the MCNs are known to be relatively resistant to glutamate receptormediated excitotoxicity (Hu et al, 1992;Bains et al, 2001). EPSC inhibition caused by dendritic release of AVP could certainly contribute to this resistance.…”

A neuronal population in hypothalamus that dramatically resists acute ischemic injury compared to neocortex

“…Is there other supporting evidence? Bains et al (2001) showed that a K ϩ current (I D ) in MNCs of PVN was responsible for resisting strong depolarization evoked by an NMDA receptor agonist, in contrast to adjacent susceptible parvocellular neurons. Inhibition of I D with 4-AP increased depolarization and resulted in death of MNCs.…”

“…Inhibition of I D with 4-AP increased depolarization and resulted in death of MNCs. Indeed, MNCs of the SON and PVN are resistant to systemic and intracranial injections of glutamate analogs, in contrast to neocortex and adjacent hypothalamic neurons (Bains et al 2001;Herman and Weigand 1986;Hu et al 1992;Schwob et al 1980). However, glutamate receptor activation is not required for the generation or propagation of AD in adult cortical slices (Anderson et al 2005;Jarvis et al 2001;Joshi and Andrew 2001;Muller and Somjen 2000;Tanaka et al 1997) or in vivo (Murphy et al 2008;Nellgard and Wieloch 1992).…”