Calmodulin: Effects of cell stimuli and drugs on cellular activation

Abstract

Drugs, hormones and neurotransmitters affect cell Ca²⁺in a variety of ways, by activating or blocking voltage- or ligand-dependent Ca²⁺channels, membrane Ca²⁺pumps, or Ca²⁺release from intracellular stores. Upon elevation, Ca²⁺usually acts either by directly stimulating enzymes such as protein kinase C (PKC) or calpain, a Ca²⁺activated protease, or by binding to a Ca²⁺-binding protein which will have restricted or multiple actions. Calmodulin (CaM) is a principal multifunctional mediator of Ca²⁺signalling in cells. CaM acts as a Ca²⁺-dependent regulator of cyclic nucleotide metabolism, protein phosphorylation-dephosphorylation cascades, Ca²⁺- and other ion transport, cytoskeletal function, cell growth and proliferation [1–3]. Detailed knowledge of the in vitroactivation of several target isoenzymes by CaM and its binding to cytoskeletal proteins is available, but knowledge concerning the in vivoor in situactivation of CaM-dependent processes in response to drugs, hormones and neurotransmitters is just emerging. Rapid activation of some CaM-dependent enzymes in response to elevated intracellular calcium ([Ca²⁺]i) has been demonstrated in situbut it is unclear whether CaM-dependent enzymes are activated globally or selectively in the cell. Recent evidence suggests that Ca²⁺and CaM-dependent physiological activities can be selectively altered depending upon cellular domains responding to stimuli.