gms | German Medical Science

Objective: Experimental subarachnoid hemorrhage (SAH) has been shown to trigger expression of Cav2.3 (R-type) calcium channels in cerebral smooth muscle cells and antagonism of R-type calcium channels prevents the pathological hypoperfusion after experimental SAH. However, the role of Cav2.3 channels in the complex delayed pathology after SAH remains unclear. We investigated the electrophysiological effects of whole blood lysate and bilirubin on recombinant Cav2.3 channels.

Method: Whole cell patch-clamp recordings were obtained from HEK-293 cells stably transfected with human Cav2.3 and Cavß3 subunits. Cells were transiently perfused with human whole blood, whole blood lysate, or micromolar concentrations of bilirubin.

Results: Whole blood lysate and bilirubin differently affected currents mediated by Cav2.3. Hemolyzed blood stimulated whole cell currents and produced irreversible hyperpolarizing shifts of half maximal activation and inactivation. Bilirubin had a similar, yet less marked effect on steady-state activation but markedly reduced peak currents measured at positive potentials.

Conclusions: Hemolysate and blood metabolites appear to modulate the function of R-type calcium channels, which are expressed throughout the CNS and in cerebrovascular myocytes after SAH. The observed effects indicate that Cav2.3 channels may be involved in the hemolysate-induced [Ca²⁺] elevation in cerebral smooth muscle cells. Further investigation will be necessary to identify components responsible for these effects. Aberrant R-type signaling may also promote hypoperfusion and contribute to neurotoxicity, as R-type channels have been shown to be involved in excitotoxicity.