CRIM 2653 Chapter Notes - Chapter 10.9: Carbonic Anhydrase Inhibitor, Acetazolamide, Hyperalgesia
23 May 2020
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Tonic Conductance and shunting inhibition
Tonic conductance is activated by low concentrations of GABApresent in the
extracellularspace. GABA can increase following intense synaptic activity (synaptic
spillover)
-GABA is also removed by glial GABA transporters which regulate tonic conductance by
ensuring low GABAin the exxtrasynaptic space
-Slide 40: at a certain point, the flow of chloride ions moves from being transported
inside to being transported outside (we move from hyperpolarizing to depolarizing)
-remember that if the equilibrium potential is equal to the membrane potential of the
cel, there will b no ion flow
-Shunting inhibition (tonic inhibition): when EGABAis close to Vm →G_A_B_A doesn’t
hyperpolarize the membrane but it reduces effect of excitatory current →cell requires
more excitation to generate AP
-persistently increases membrane conductance
-KCC2 is a K+/Cl- symporter that removes chloride ions from the cell. It relies on the
potassium gradients for function. We actively pump out chloride ions along with
symport with potassium ions (going down potassium concentration gradient)
-dominant source of chloride regulation in mature cells
-Loss of synaptic inhibition leads to chronic pain-GABA inhibition is dependent onratio
of intracellular Cl-to extracellular Cl-(concentration gradient)
both hyperpolarization& shunting inhibitionrequires sufficient KCC2 activity. Collapse
of Cl-gradient →chronic pain
-Loss of KCC2 contributes to: chronic pain, opioid-induced hyperalgesia. Decreased
KCC@ may also ontribute to autism, schizophrenia, epilepsy, spasticity
How can we treat KCC2 downregulation?
-Attempt to restore inhibition with decrease in intracellular HCO3
-Acetazolamide is a carbonic anhydrase inhibitor
Document Summary
Tonic conductance is activated by low concentrations of gabapresent in the extracellularspace. Gaba can increase following intense synaptic activity (synaptic spillover) Gaba is also removed by glial gaba transporters which regulate tonic conductance by ensuring low gabain the exxtrasynaptic space. Slide 40: at a certain point, the flow of chloride ions moves from being transported inside to being transported outside (we move from hyperpolarizing to depolarizing) Remember that if the equilibrium potential is equal to the membrane potential of the cel, there will b no ion flow. Shunting inhibition (tonic inhibition): when egabais close to vm g_a_b_a doesn"t hyperpolarize the membrane but it reduces effect of excitatory current cell requires more excitation to generate ap. Kcc2 is a k+/cl- symporter that removes chloride ions from the cell. It relies on the potassium gradients for function. We actively pump out chloride ions along with symport with potassium ions (going down potassium concentration gradient) Dominant source of chloride regulation in mature cells.
