Calcium-activated potassium channel SK1- and IK1-like immunoreactivity in injured human sensory neurones and its regulation by neurotrophic factors.
Calcium-activated potassium ion channels SK and IK (small and intermediate conductance, respectively) may be important in the pathophysiology of pain following nerve injury, as SK channels are known to impose a period of reduced excitability after each action potential by afterhyperpolarization. We studied the presence and changes of human SK1 (hSK1)- and hIK1-like immunoreactivity in control and injured human dorsal root ganglia (DRG) and peripheral nerves and their regulation by key neurotrophic factors in cultured rat sensory neurones. Using specific antibodies, hSK-1 and hIK-1-like immunoreactivity was detected in a majority of large and small/medium-sized cell bodies of human DRG. hSK1 immunoreactivity was decreased significantly in cell bodies of avulsed human DRG (n = 8, surgery delay 8 h to 12 months). There was a decrease in hIK1-like immunoreactivity predominantly in large cells acutely (<3 weeks after injury), but also in small/medium cells of chronic cases. Twenty-three injured peripheral nerves were studied (surgery delay 8 h to 12 months); in five of these, hIK1-like immunoreactivity was detected proximally but not distally to injury, whereas neurofilament staining confirmed the presence of nerve fibres in both regions. These five nerves, unlike the others, had all undergone Wallerian degeneration previously and the loss of hIK1-like immunoreactivity may therefore reflect reduced axonal transport of this ion channel across the injury site in regenerated fibres, as well as decreased expression in the cell body. In vitro studies of neonatal rat DRG neurones showed that nerve growth factor (NGF) significantly increased the percentage of hSK1-positive cells, whereas neurotrophin 3 (NT-3) and glial cell line-derived neurotrophic factor (GDNF) failed to show a significant effect. NT-3 stimulated hIK1 expression, while NGF and GDNF were ineffective. As expected, NGF increased expression of the voltage-gated sodium channel SNS1/PN3 in this system. Decreased retrograde transport of these neurotrophic factors in injured sensory neurones may thus reduce expression of these ion channels and increase excitability. Blockade of IK1-like and other potassium channels by aminopyridines (4-AP and 3,4-DAP) may also explain the paraesthesiae induced by these medications. Selective potassium channel openers are likely to represent novel therapies for pain following nerve injury.
Boettger
M K
MK
Peripheral Neuropathy Unit, Department of Neurology, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK.
Till
S
S
Chen
M X
MX
Anand
U
U
Otto
W R
WR
Plumpton
C
C
Trezise
D J
DJ
Tate
S N
SN
Bountra
C
C
Coward
K
K
Birch
R
R
Anand
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000293:injuries / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D020932:Nerve Growth Factor / Q000494:pharmacology*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D020933:Neurotrophin 3 / Q000494:pharmacology*; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D051381:Rats; D017208:Rats, Wistar; D051640:Small-Conductance Calcium-Activated Potassium Channels
D000906:Antibodies; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; C496894:KCNN1 protein, human; C496896:Kcnn1 protein, rat; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D020932:Nerve Growth Factor