TY - JOUR

T1 - Pharmacological modulation of SK3 channels

AU - Grunnet, M

AU - Jespersen, Thomas

AU - Angelo, K

AU - Frøkjaer-Jensen, C

AU - Klaerke, D A

AU - Olesen, S P

AU - Jensen, B S

PY - 2001/6/1

Y1 - 2001/6/1

N2 - Small-conductance, calcium-activated K+ channels (SK channels) are voltage-insensitive channels that have been identified molecularly within the last few years. As SK channels play a fundamental role in most excitable cells and participate in afterhyperpolarization (AHP) and spike-frequency adaptation, pharmacological modulation of SK channels may be of significant clinical importance. Here we report the functional expression of SK3 in HEK293 and demonstrate a broad pharmacological profile for these channels. Brain slice studies commonly employ 4-aminopyridine (4-AP) to block voltage-dependent K+ channels or a methyl derivative of bicuculline, a blocker of gamma-aminobutyric acid (GABA)-gated Cl- channels, in order to investigate the role of various synapses in specialized neural networks. However, in this study both 4-AP and bicuculline are shown to inhibit SK3 channels (IC50 values of 512 microM and 6 microM, respectively) at concentrations lower than those used for brain slice recordings. Riluzole, a potent neuroprotective drug with anti-ischemic, anticonvulsant and sedative effects currently used in the treatment of amyotrophic lateral sclerosis, activates SK3 channels at concentrations of 3 microM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 10 microM (n=6).

AB - Small-conductance, calcium-activated K+ channels (SK channels) are voltage-insensitive channels that have been identified molecularly within the last few years. As SK channels play a fundamental role in most excitable cells and participate in afterhyperpolarization (AHP) and spike-frequency adaptation, pharmacological modulation of SK channels may be of significant clinical importance. Here we report the functional expression of SK3 in HEK293 and demonstrate a broad pharmacological profile for these channels. Brain slice studies commonly employ 4-aminopyridine (4-AP) to block voltage-dependent K+ channels or a methyl derivative of bicuculline, a blocker of gamma-aminobutyric acid (GABA)-gated Cl- channels, in order to investigate the role of various synapses in specialized neural networks. However, in this study both 4-AP and bicuculline are shown to inhibit SK3 channels (IC50 values of 512 microM and 6 microM, respectively) at concentrations lower than those used for brain slice recordings. Riluzole, a potent neuroprotective drug with anti-ischemic, anticonvulsant and sedative effects currently used in the treatment of amyotrophic lateral sclerosis, activates SK3 channels at concentrations of 3 microM and above. Amitriptyline, a tricyclic antidepressive widely used clinically, inhibits SK3 channels with an IC50 of 39.1 +/- 10 microM (n=6).

KW - 4-Aminopyridine

KW - Amitriptyline

KW - Animals

KW - Antidepressive Agents, Tricyclic

KW - Apamin

KW - Bicuculline

KW - Cell Line

KW - Humans

KW - Neuroprotective Agents

KW - Potassium Channels

KW - Potassium Channels, Calcium-Activated

KW - Rats

KW - Riluzole

KW - Small-Conductance Calcium-Activated Potassium Channels

M3 - Journal article

C2 - 11378158

VL - 40

SP - 879

EP - 887

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

IS - 7

ER -