Smart Ca²⁺ decoding by the calmodulin/Ca channel complex

Abstract

Calmodulin (CaM) demonstrates biologically critical regulation of Ca_V1-2 Ca²⁺ channels. This talk explores three aspects of the powerful Ca²⁺ decoding that CaM exhibits in this context. (1) We summarize the current model of CaM/channel modulation, wherein Ca²⁺-free CaM (apoCaM) preassociates with channels, and subsequent Ca²⁺ influx drives conformational changes that induce regulation. Ca²⁺ binding to the individual lobes of CaM autonomously trigger different forms of modulation. The N-lobe usually responds to Ca²⁺ entry through sources other than the channel being regulated (global Ca²⁺ preference); the C-lobe favors Ca²⁺ entering via the regulated channel itself (local Ca²⁺ preference). (2) We describe a novel module that transforms the local/global Ca²⁺ preference of regulation. This module furnishes a vital clue (or 'Rosetta stone') for Ca²⁺ decoding. To start, Ca_V2.2 channels exhibit N-lobe Ca²⁺-dependent inactivation (CDI) with a global Ca²⁺ preference. Switching a small segment of Ca_V1.2 or Ca_V1.3 into Ca_V2.2 produces chimeric channels where CDI now has a local preference. Conversely, Ca_V1.3 channels exhibit an N-lobe CDI with a local preference, and deletion of this same portion within Ca_V1. 3 switches the Ca²⁺ preference from local to global. The key element of this Rosetta module is a Ca²⁺/CaM binding site. (3) This Rosetta module implicates a simple decoding mechanism wherein Ca²⁺ preference is specified by the ratio of channel affinities for Ca²⁺/CaM versus apoCaM. Indeed, the transforming actions of the CaM-binding Rosetta module satisfy stringent predictions of this new mechanism. [J Physiol Sci. 2007;57 Suppl:S14]