Altered Expression and Function of Ryanodine Receptors and FKBP12.6 after Subarachnoid Hemorrhage: More than Meets the Eye

Abstract

Subarachnoid hemorrhage decreases the expression of ryanodine receptors and increases the expression of the immunophilin, FK506-binding protein (FKBP)12.6 in cerebrovascular smooth muscle cells, reducing the occurrence of Ca²⁺ sparks, limiting negative feedback regulation of cerebrovascular tone and promoting vasospasm. However, given the large number of binding partners with which FKBP12.6 and related proteins interact, it appears likely that the altered expression of this immunophilin will have a broader impact on cerebrovascular smooth muscle function. In addition, the mechanisms responsible for the measured changes in expression of ryanodine receptors and FKBP12.6 yet remain unknown. These topics should prove to be fertile ground for future studies.

Ion channels have a central role in regulating the function of blood vessels in the brain and elsewhere in the body (Jackson, 2005; Wellman, 2006). The plasma membrane and intracellular ion channels are the primary sources of Ca²⁺ that regulate vascular smooth muscle tone (Hill et al, 2001) and gene expression (Barlow et al, 2006). In addition, ion channels importantly contribute to the determination and regulation of smooth muscle membrane potential, which, in turn, regulates the function of voltage-gated Ca²⁺ channels (Jackson, 2005) and the release of intracellular Ca²⁺ (Liu et al, 2009). Subarachnoid hemorrhage (SAH) has previously been shown to alter the expression and function of several ion channels in cerebrovascular smooth muscle cells, including downregulation of voltage-gated K⁺ channels and increased expression and function of voltage-gated Ca²⁺ channels, changes that contribute to cerebral vasospasm that accompanies the hemorrhage (Wellman, 2006). The study by Koide et al (2011) in this issue of the Journal of Cerebral Blood Flow and Metabolism shows that the effects of SAH are not limited to plasma membrane ion channels, but extend to channels located in the endoplasmic reticulum. Using posterior cerebral and cerebellar arteries, they provide novel and compelling evidence that the expression and function of smooth muscle ryanodine receptors (RyR) are reduced, whereas the expression of the modulatory protein, FK506-binding protein (FKBP)12.6, is increased after exposure of the vessels to autologous blood. This study is noteworthy for at least two reasons. First, it identifies an additional mechanism that may contribute to SAH-induced vasospasm. This, in turn, provides new therapeutic targets to combat this pathology. Second, their finding that FKBP12.6 expression is elevated suggests that a number of additional, unrecognized signaling pathways may also be impacted after SAH. FKBP12.6 is a member of the immunophilin family of proteins, which bind the immunosuppressive drugs, FK506 and rapamycin. In addition to binding to RyR2 and stabilizing the closed state of these channels, FKBP12.6 has cis-trans-prolylisomerase activity and interacts with the phosphatase, calcineurin (Marks, 1996). A closely related immunophilin, FKBP12, which is also expressed in smooth muscle, interacts with mTOR (mammalian target for rapamycin) impacting cellular proliferation and inflammatory responses, inhibits transforming growth factor-β receptor signaling (Giordano et al, 2008), and modulates Inositol 1,4,5-trisphosphate receptors (IP₃R) (MacMillan and McCarron, 2009). In smooth muscle, FKBP12 participates in the regulation of Ca²⁺ release through IP₃R by interactions with calcineurin and mTOR (MacMillan and McCarron, 2009), which obviously impact many other signaling pathways. Thus, SAH-induced changes in FKBP12.6 may have much broader effects on vascular smooth muscle than simply affecting RyR function and limiting negative-feedback regulation of cerebrovascular tone. The mechanisms by which SAH produces the observed changes in RyR and FKBP12.6 expression and function, as well as the magnitude of the contribution of RyR downregulation and FKBP12.6 upregulation to SAH-induced vasospasm are also to be established. These issues were not addressed by Koide et al (2011), but should prove to be fertile ground for future studies.