T-lymphocytes require calcium entry though the plasma membrane for their activation and function. Recently, several routes for calcium entry through the T cell plasma membrane after activation have been described. These include CRAC channels (Calcium Release of Activated Channels), TRP channels (Transient Receptor Potential) and inositol-1,4,5-trisphosphate receptors (IP3R). Herein we are proposing the emergence of a new fourth route for calcium entry, composed of Cav channels (also known as L-type voltage gated calcium channels) and their regulator scaffold protein AHNAK1 (AHNAK/Desmoyokin). In excitable cells, such as neurons or muscle cells, Cav calcium channels constitute the major route for calcium entry. We have previously published that both helper (CD4+) and killer (CD8+) T cells express high levels of Cav1 alpha1 subunits (alpha 1S, -1C, -1D and -1F) and AHNAK1 after their differentiation and require these molecules for calcium entry during an immune response.
This proposal aims to study the molecular mechanism by which this pathway is induced and functions. My preliminary evidence suggest that Cav channel calcium currents are induced by TCR stimulation, not by voltage depolarization, as described in excitable cells. Further studies proposed here are required to study this phenomenon.
In this proposal, we will describe the observations and open questions, which ultimately suggests the involvement of multiple consecutive routes for calcium entry into lymphocytes, one of which is apparently mediated by Cav channels and AHNAK1.
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