Suppression of the Expression of a Pancreatic -Cell Form of the Kinesin Heavy Chain by Antisense Oligonucleotides Inhibits Insulin Secretion from Primary Cultures of Mouse -Cells

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Abstract
Granular/vesicular transport is thought to be supported by micro- tubule-based force-generating adenosine triphosphatases such as ki- nesin. Kinesin is a motor molecule that has been well studied in brain and other neuronal tissues. Although vesicular transport is important for pancreatic b-cell secretory activities, the role of kinesin in b-cell function has not been investigated. It is hypothesized that kinesin functions as a translocator that associates with both microtubules and insulin-containing granules in b-cells and transports the secretory granules from deep within the cytoplasm, where insulin is synthe- sized and processed, to the surface of b-cells upon secretory stimu- lation. To test this hypothesis, a mouse b-cell kinesin heavy chain complementary DNA was cloned and sequenced. Kinesin expression in primary cultures of mouse b-cells then was selectively suppressed by antimouse b-cell kinesin heavy chain antisense oligonucleotide treatment. Analysis of insulin secretion determined that the basal level of insulin secretion from the treated cells was decreased by 50%. Furthermore, glucose-stimulated insulin release from treated b-cells was reduced by almost 70% after suppression of kinesin expression by antisense treatment. The findings from this study provide the first direct evidence that kinesin, a microtubule-based motor protein, plays an important role in insulin secretion. (Endocrinology 138: 1979 - 1987, 1997)

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