Polyamines regulate calcium fluxes in a rapid plasma membrane response

Abstract

Activation of cell-surface receptors often evokes changes in Ca²⁺ fluxes leading to an increase in cytosolic Ca²⁺, a generally accepted mediator of many cell responses^1–3. The molecular mechanisms by which surface agonists elicit these changes in Ca²⁺ flux have remained elusive. An increase in the polyamines putrescine, spermidine and spermine, and their rate-regulating, synthetic enzyme ornithine decarboxylase (ODC), is one of the earliest events that occur during cell growth, replication and differentiation^4–6. However, the precise physiological roles of the polyamines remain enigmatic^4–6. Recently, we found that testosterone induces an early (<60s), Ca²⁺- and receptor-dependent stimulation of endocytosis, hexose transport and amino acid transport in mouse kidney cortex involving the proximal tubules⁷. This response is associated with increased Ca²⁺ fluxes and a mobilization of intracellular calcium, and is thought to represent a direct, receptor-mediated action of testosterone on the surface membrane^7,8. Polyamine synthesis was previously found to be essential for the long-term effects of testosterone on mouse kidney⁹. We now report that testosterone evokes a rapid (<30 s), transient increase in ODC activity and a sustained increase in polyamines in kidney cortex. This polyamine synthesis is obligatory for stimulation of membrane transport functions and Ca²⁺ fluxes. These findings form the basis for a new theory of information flow in stimulus–response coupling in which the polyamines serve as messengers to generate a Ca²⁺ signal by increasing Ca²⁺ influx and mobilizing intracellular calcium via a cation-exchange reaction.