Molecular and functional determinants of Ca²⁺ signaling microdomains

Calcium homeostasis is a finely tuned process that occurs within narrowly defined physiological parameters. Compartmentalization of the calcium signaling complex involved in sensing, generating, and propagating the signal ensures a rapid response to the stimuli and fidelity of the response. This is achieved by assembling the key components involved in this process into a closely associated complex. Such a complex has been well established in the case of store-operated calcium entry (SOCE), a critical Ca²⁺ signaling mechanism that regulates a variety of cellular functions. Membrane domains (e.g., the plasma membrane lipid raft domains) as well as specific proteins (e.g., caveolin-1) provide scaffolds for assembly of signaling complexes associated with Ca ²⁺ entry, which include not only the channels mediating Ca ²⁺ flux but also the regulatory proteins and downstream sensors. In this chapter, we will discuss the function of TRPC1 (a channel involved in SOCE) and organization of TRPC1 channel complexes, involving the role of newly identified proteins, Orai1 and STIM1. Finally, we will consider recent advances in the field that substantiate and extend our understanding of the molecular components which determine the assembly and compartmentalization of Ca ²⁺ entry signals.