APPS November 2002 Meeting Abstract 1148

In lymphatic smooth muscle inositol 1,4,5-trisphosphate (IP₃) dependent Ca²⁺ release from intracellular Ca²⁺ stores has been shown to act as a pacemaker generating membrane depolarization leading to muscle vasomotion¹. Pacemaking in lymphatic smooth muscle involves synchronization of Ca²⁺ store release, a process which appears to be enhanced by agonists known to increase synthesis of IP₃ and inhibited by blocking Ca²⁺entry by agents such as nifedipine². Here we present a theoretical study of experimental data presented in accompanying abstract². We base our analysis on the known information that Ca²⁺ release from IP₃operated Ca²⁺stores has a biphasic dependence on both cytosolic IP₃ ([IP₃]_i) and Ca²⁺ concentration ([Ca²⁺]_i)³, and that Ca²⁺entry through voltage-gated Ca²⁺channels causes significant increase in [Ca²⁺]_i. We begin by proposing that the IP₃operated Ca²⁺stores in the lymphatic smooth muscle have a heterogeneous response to both Ca²⁺ and IP₃. A model based on the interplay of the heterogeneous store population and Ca²⁺increase caused due to Ca²⁺influx through the voltage-gated channels provides a fundamental model to explain the experimental observations². In this model, stores interact and synchronise through two mechanisms arising out of local store Ca²⁺release. First, the released Ca²⁺diffuse to activate and/or synchronise the release cycle of adjacent stores. Second, the inward current/depolarization resulting from store release has a long-range influence on activation of L-type Ca²⁺channels, and the resultant Ca²⁺entry activates/synchronizes stores more globally.