Targeted delivery of glycine receptors to excitable cells
The invention provides a method of modulating electrophysiological activity of an excitable cell. The method involves causing exogenous expression of a glycine receptor (GlyR) protein in an excitable cell of a subject. Thereafter, the excitable cell is exposed to an allosteric modulator of the GlyR protein. Modulation of the exogenous GlyR protein (an ion channel) in response to the allosteric modulator modulates the electrophysiological activity of the excitable cell. The method can be used to control pain in a subject. The invention further provides a replication-defective HSV vector comprising an expression cassette encoding a GlyR protein, stocks and pharmaceutical compositions containing such vectors, and a transgenic animal.
1. A method of modulating the electrophysiological activity of a peripheral neuron within a subject comprising inducing expression of a glycine receptorα1 (GlyRα1) protein in a peripheral neuron of a subject by introducing a genetic vector into the peripheral neuron, said vector comprising a nucleic acid encoding the GlyRα1 protein in operable linkage to a promoter, to express the GlyRα1 protein in the peripheral neuron, and subsequently exposing the peripheral neuron to an allosteric modulator of the GlyRα1 protein, wherein the electrophysiological activity of the peripheral neuron is modulated by administration of the allosteric modulator.
2. The method of claim 1 , wherein the peripheral neuron is a sensory neuron associated with the sensation of pain.
3. The method of claim 1 , wherein the GlyRα1 protein comprises a mutein of a GlyRα1 subunit.
4. The method of claim 3 , wherein the mutein converts the GlyRα1 to a cationic channel.
5. The method of claim 3 , wherein the mutein has altered sites for zinc potentiation or zinc inhibition, anesthetic potentiation, or affinity for ligands.
6. The method of claim 1 , wherein the genetic vector is a replication-defective HSV vector.
7. The method of claim 1 , wherein the allosteric modulator is an agonist of the GlyRα1 protein.
8. The method of claim 7 , wherein the agonist comprises glycine.
9. The method of claim 1 , wherein the subject is human.
10. The method of claim 3 , wherein the mutein exhibits altered sensitivity and/or selectivity for ligands, and wherein the allosteric modulator is an agonist of the mutein.
11. The method of claim 10 , wherein the agonist comprises ivermectin.
12. The method of claim 1 , wherein the allosteric modulator comprises ivermectin.
13. The method of claim 3 , wherein the allosteric modulator comprises ivermectin.
14. The method of claim 1 , wherein the allosteric modulator comprises glycine.