Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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MOLECULAR IDENTIFICATION OF FUNCTIONAL K+ CHANNELS


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Xenopus laevis provides an ideal animal model for the study of the developing vertebrate nervous system as the developmental stages in this species have been extremely well characterized. In addition, the use of standard in vitro fertilization techniques allows the production of embryos of any age whose neurons can be examined for the acquisition of electrical excitability. Amphibian spinal neurons first demonstrate action potentials at the neural plate stage (22 hr after fertilization). These impulses are calcium-dependent and of long duration. During the following 24 hours, the form of the action potential changes markedly, becoming the brief, sodium- driven spike characteristic of mature neurons. Previous work has shown that the transition from the mature to the immature wave-form is primarily due to the maturation of a delayed rectifier potassium current. During this develop mental transition the calcium current changes little while the sodium current doubles in density. The potassium current, however, triples in density and also demonstrates faster kinetics. Mathematical reconstruction of action potentials has also shown that the change in the shape of the impulse can be accounted for by the alternation in potassium current properties. The molecular bases underlying these stereotyped changes remain, as yet, unknown. A goal of my project is to match the molecular identities of the potassium channels cloned thus far in Xenopus with the functional potassium channel populations recorded from developing amphibian spinal neurons. Transcripts from two of the four known alpha subunit genes in Xenopus, Kv1.1 (a member of the Shaker-like subfamily) and Kv2.2 (a member of the Shab like subfamily), have been shown by in situ hybridization and single-cell reverse transcriptase PCR to be present in the developing amphibian spinal cord. In addition, these channels induce delayed rectifier potassium currents when expressed in the Xenopus oocyte. Kv1.1 and Kv2.2 gene products are thus likely candidates for the induction of currents leading to the shortening and maturation of the action potential.

Thw work outlined above should allow the identification of endogenous functional single channels that contain Kvc1 and/or Kv2 subunits. This is significant as to date, no experiments have matched the molecular identity of gene with a functional channel population recorded from the developing spinal cord. The next step would be an elucidation of the mechanisms involved in the transcription of the gene of interest - i.e. a determination of why that particular gene is transcribed in a specific neuronal subset at a certain developmental stage. Ultimately such knowledge will provide a more complete understanding of the events involved in the acquisition of electrical excitability and hence the possibility of designing more effective therapies for the treatment of disorders of the developing nervous system and those disorders due to improper due to improper excitation such as epilepsy.
Collapse sponsor award id
F30MH011349

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Collapse start date
1996-10-17

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