Emerging roles of L-type voltage-gated and other calcium channels in T lymphocytes

Abstract

In T lymphocytes, calcium ion controls a variety of biological processes including development, survival, proliferation, and effector functions. These distinct and specific roles are regulated by different calcium signals, which are generated by various plasma membrane calcium channels. The repertoire of calcium-conducting proteins in T lymphocytes includes store-operated CRAC channels, transient receptor potential channels, P2X channels, and L-type voltage-gated calcium (Cav1) channels. In this paper, we will focus mainly on the role of the Cav1 channels found expressed by T lymphocytes, where these channels appear to operate in a T cell receptor stimulation-dependent and voltage sensor independent manner. We will review their expression profile at various differentiation stages of CD4 and CD8 T lymphocytes. Then, we will present crucial genetic evidence in favor of a role of these Cav1 channels and related regulatory proteins in both CD4 and CD8 T cell functions such as proliferation, survival, cytokine production, and cytolysis. Finally, we will provide evidence and speculate on how these voltage-gated channels might function in the T lymphocyte, a non-excitable cell.

Keywords: CD4 T cells; CD8 T cells; CRAC channel; Cav1 channels; calcium channels.

Figure 1

A model for coordinated control of Ca_v1 and ORAI1 channels in T lymphocytes. Antigen encounter by T cells results in the activation of numerous pathways including the Ca²⁺ pathway. Mechanisms of Ca²⁺ influx through two major Ca²⁺-permeable channels, Ca_v1 and ORAI1, are depicted in this scheme. During the course of biological functions that require activation of the STIM/ORAI pathway (such as effector functions and apoptosis), STIM1 blocks Ca_v1 channel activity and all depending T cell functions. In contrast, this inhibitory effect would be lifted when Ca_v1-dependent T cell functions (such as survival and naïve T cell activation) take place (, , , , , , –59, 77, 78). It is, however, important to point out that the crosstalk described in this model was shown solely for Ca_v1.2 channel, and no information is available to date for the relationship between STIM and other Ca_v1 channels. TCR, T cell receptor; Ca_v, voltage-gated Ca²⁺ channels; ER, endoplasmic reticulum; IP3, inositol-1,4,5-trisphosphate; SERCA, sarco-endoplasmic reticulum Ca²⁺-ATPase; STIM1, stromal interaction molecule 1; PLCγ1, phospholipase Cγ1; MAP kinase, Mitogen-activated protein kinase; PKC, protein kinase C; NFkB, nuclear factor kB; AP-1, activator protein-1; and NFAT, nuclear factor of activated T cells.