Arteries: STIMulating blood pressure
Arteries contain smooth muscle cells, which contract and relax to change the diameter of blood vessels, controlling blood flow to ensure that cells get the correct amount of oxygen and nutrients. To understand how blood flow and blood pressure are regulated, it is important to characterize signaling mechanisms that occur in these cells and change how they contract and relax. This information can then be used to determine what happens to these signaling pathways during cardiovascular diseases, such as hypertension and stroke, and develop new therapies to treat these life-threatening conditions.
In many cell types, including arterial smooth muscle cells, the plasma membrane surrounding the cell lies only a few nanometers away from the membrane of an organelle known as the endoplasmic reticulum, or in the case of muscle cells, the sarcoplasmic reticulum (SR/ER). The tiny cytoplasmic regions between these two membranes, called peripheral coupling sites, have their own microenvironment, where local communication can occur between proteins without impacting the rest of the cell. In muscle cells, these regions are involved in calcium signaling, which is responsible for regulating both contraction and relaxation (Figure 1). Despite the importance of peripheral coupling sites, how they form remains unclear.
In many cell types, the membrane of the SR/ER contains proteins called Stromal Interaction Molecules (STIMs). These proteins are well known for playing a role in store operated calcium entry (SOCE), a mechanism that replenishes the calcium in the SR/ER. When the calcium concentration inside the SR/ER decreases, STIMs elongate and interact with ion channels on the plasma membrane termed Orai. These channels have many roles, including helping refill the SR/ER with calcium (Prakriya and Lewis, 2015).
This canonical STIM signaling pathway, however, does not occur in healthy arterial smooth muscle cells, which – despite having STIMs – have very little Orai and generate little to no SOCE (Krishnan et al., 2022; Potier et al., 2009; Xi et al., 2008). This apparent paradox has raised a decade-old question: what is the function of STIMs in arterial smooth muscle cells? Now, in eLife, Scott Earley and colleagues at the University of Nevada, the University of Pittsburgh and Pennsylvania State University – with Vivek Krishnan, Sher Ali, Albert Gonzales and Pratish Thakore as joint first authors – report that one member of the STIM family, STIM1, plays an important role in arterial smooth muscle cells that is different from the canonical STIM pathway (Krishnan et al., 2022).
Krishnan et al. first genetically modified mice so that they would not produce STIM1 in their smooth muscle cells. They then used state-of-the-art microscopy techniques, which can image cellular structures only a few nanometers in size, to establish that the arterial smooth muscle cells of these mice had fewer peripheral coupling sites. Loss of STIM1 also altered how some ion channels in the plasma membrane and the SR/ER membrane were clustered, and reduced the ability of calcium released from the SR/ER to activate ion channels in the plasma membrane. These changes made arterial smooth muscle cells less able to contract, which meant that the mice had relaxed arteries and lower blood pressure. These results demonstrate how these microenvironments within arterial smooth muscle cells have global implications. Specifically, the findings suggest that STIM1 may be regulating blood pressure by helping to maintain peripheral coupling sites in arterial smooth muscle cells.
One open question is how this new role for STIM1 compares to its more established canonical signaling pathway. This is especially important given that when arteries become injured, arterial smooth muscle cells shift into a non-contractile, proliferative phenotype to help repair the damage. In this state, these cells use canonical STIM1-dependent SOCE, which is also upregulated during hypertension (Potier et al., 2009; Zhang et al., 2011; Johnson et al., 2020). This implies that arterial smooth muscle cells are capable of using STIM1 in its canonical and non-canonical roles depending on their state (Figure 1).
Further research will be needed to determine exactly how the absence of STIM1 leads to the loss of peripheral coupling sites. One explanation is that STIM1 normally acts as a bridge between the SR/ER and plasma membranes, helping to maintain these tiny regions. Another could be that STIM1 interacts with proteins other than Orai in the plasma membrane, as shown in other cell types (Berlansky et al., 2021). Such interactions may not only form peripheral coupling sites, but also stabilize clusters of these membrane proteins.
Several other questions remain. First, experimental limitations meant it was not possible to directly measure the properties of STIM1 clusters at peripheral coupling sites: doing so could shed light on how these regions form. Second, removing STIM1 from arterial smooth muscle cells reduced the volume of the SR/ER in these cells, and the mechanisms that govern this change are uncertain. Earlier work from some of the scientists involved in the Krishnan et al. study suggested that a protein called junctophilin-2 also maintains peripheral coupling sites (Pritchard et al., 2019). It would be interesting to determine if STIM1 and junctophilin-2 support the same peripheral coupling sites or act at different regions, and whether they interact with different proteins.
In conclusion, Krishnan et al. provide fascinating observations into the non-canonical roles of STIM1 in arterial smooth muscle cells, and how this modulates the ability of arteries to contract, relax and regulate blood pressure. As with all great research, these observations raise as many questions as they answer, making this an exciting area to follow – stay tuned!
References
-
More than just simple interaction between STIM and Orai proteins: CRAC channel function enabled by a network of interactions with regulatory proteinsInternational Journal of Molecular Sciences 22:E471.https://doi.org/10.3390/ijms22010471
-
Store-operated calcium channelsPhysiological Reviews 95:1383–1436.https://doi.org/10.1152/physrev.00020.2014
-
Orai1-mediated I (CRAC) is essential for neointima formation after vascular injuryCirculation Research 109:534–542.https://doi.org/10.1161/CIRCRESAHA.111.246777
Article and author information
Author details
Publication history
Copyright
© 2022, Garrud and Jaggar
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 919
- views
-
- 61
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Structural Biology and Molecular Biophysics
Chemical synapses are the major sites of communication between neurons in the nervous system and mediate either excitatory or inhibitory signaling. At excitatory synapses, glutamate is the primary neurotransmitter and upon release from presynaptic vesicles, is detected by postsynaptic glutamate receptors, which include ionotropic AMPA and NMDA receptors. Here, we have developed methods to identify glutamatergic synapses in brain tissue slices, label AMPA receptors with small gold nanoparticles (AuNPs), and prepare lamella for cryo-electron tomography studies. The targeted imaging of glutamatergic synapses in the lamella is facilitated by fluorescent pre- and postsynaptic signatures, and the subsequent tomograms allow for the identification of key features of chemical synapses, including synaptic vesicles, the synaptic cleft, and AuNP-labeled AMPA receptors. These methods pave the way for imaging brain regions at high resolution, using unstained, unfixed samples preserved under near-native conditions.
-
- Structural Biology and Molecular Biophysics
The calcium-activated TMEM16 proteins and the mechanosensitive/osmolarity-activated OSCA/TMEM63 proteins belong to the Transmembrane Channel/Scramblase (TCS) superfamily. Within the superfamily, OSCA/TMEM63 proteins, as well as TMEM16A and TMEM16B, are thought to function solely as ion channels. However, most TMEM16 members, including TMEM16F, maintain an additional function as scramblases, rapidly exchanging phospholipids between leaflets of the membrane. Although recent studies have advanced our understanding of TCS structure–function relationships, the molecular determinants of TCS ion and lipid permeation remain unclear. Here, we show that single mutations along the transmembrane helix (TM) 4/6 interface allow non-scrambling TCS members to permeate phospholipids. In particular, this study highlights the key role of TM 4 in controlling TCS ion and lipid permeation and offers novel insights into the evolution of the TCS superfamily, suggesting that, like TMEM16s, the OSCA/TMEM63 family maintains a conserved potential to permeate ions and phospholipids.