Arteries: STIMulating blood pressure

The protein STIM1 helps to maintain membrane coupling sites in smooth muscle cells that regulate arterial contractility and blood pressure.
  1. Tessa AC Garrud
  2. Jonathan H Jaggar  Is a corresponding author
  1. Department of Physiology, University of Tennessee Health Science Center, United States

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.

STIM1 performs distinct functions in contractile and proliferative arterial smooth muscle cells.

In contractile smooth muscle cells (left), local increases in intracellular calcium concentration occur at peripheral coupling sites, allowing signaling to take place between proteins located in the SR/ER membrane and the plasma membrane without interfering with the rest of the cell. This signaling mechanism regulates smooth muscle cells within the walls of arteries, which contract and relax to modulate how much blood can flow to organs, controlling systemic blood pressure. Krishnan et al. found that loss of STIM1 reduces peripheral coupling sites in contractile arterial smooth muscle cells. This affects local signaling mechanisms, leading to over-dilated vessels and a decrease in blood pressure. Injury or disease of the vasculature (right) can shift arterial smooth muscle cells into a non-contractile, proliferative and migratory state. In this state, STIM1 does not maintain peripheral coupling sites, and instead takes on its canonical role inducing store-operated calcium entry (SOCE), which stimulates cells to multiply and migrate, altering the structure of blood vessels.

Image credit: Figure created using BioRender.

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

Article and author information

Author details

  1. Tessa AC Garrud

    Tessa AC Garrud is in the Department of Physiology, University of Tennessee Health Science Center, Memphis, United States

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7900-7939
  2. Jonathan H Jaggar

    Jonathan H Jaggar is in the Department of Physiology, University of Tennessee Health Science Center, Memphis, United States

    For correspondence
    jjaggar@uthsc.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1505-3335

Publication history

  1. Version of Record published: March 24, 2022 (version 1)

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

  • 454
    Page views
  • 53
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

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)

  1. Tessa AC Garrud
  2. Jonathan H Jaggar
(2022)
Arteries: STIMulating blood pressure
eLife 11:e77978.
https://doi.org/10.7554/eLife.77978

Further reading

    1. Structural Biology and Molecular Biophysics
    Shreyas Bhat, Ali El-Kasaby ... Walter Sandtner
    Research Article Updated

    The serotonin transporter (SERT/SLC6A4) is arguably the most extensively studied solute carrier (SLC). During its eponymous action – that is, the retrieval of serotonin from the extracellular space – SERT undergoes a conformational cycle. Typical inhibitors (antidepressant drugs and cocaine), partial and full substrates (amphetamines and their derivatives), and atypical inhibitors (ibogaine analogues) bind preferentially to different states in this cycle. This results in competitive or non-competitive transport inhibition. Here, we explored the action of N-formyl-1,3-bis (3,4-methylenedioxyphenyl)-prop-2-yl-amine (ECSI#6) on SERT: inhibition of serotonin uptake by ECSI#6 was enhanced with increasing serotonin concentration. Conversely, the KM for serotonin was lowered by augmenting ECSI#6. ECSI#6 bound with low affinity to the outward-facing state of SERT but with increased affinity to a potassium-bound state. Electrophysiological recordings showed that ECSI#6 preferentially interacted with the inward-facing state. Kinetic modeling recapitulated the experimental data and verified that uncompetitive inhibition arose from preferential binding of ECSI#6 to the K+-bound, inward-facing conformation of SERT. This binding mode predicted a pharmacochaperoning action of ECSI#6, which was confirmed by examining its effect on the folding-deficient mutant SERT-PG601,602AA: preincubation of HEK293 cells with ECSI#6 restored export of SERT-PG601,602AA from the endoplasmic reticulum and substrate transport. Similarly, in transgenic flies, the administration of ECSI#6 promoted the delivery of SERT-PG601,602AA to the presynaptic specialization of serotonergic neurons. To the best of our knowledge, ECSI#6 is the first example of an uncompetitive SLC inhibitor. Pharmacochaperones endowed with the binding mode of ECSI#6 are attractive, because they can rescue misfolded transporters at concentrations, which cause modest transport inhibition.

    1. Biochemistry and Chemical Biology
    2. Structural Biology and Molecular Biophysics
    Jiemin Shen, Azaan Saalim Wilbon ... Yaping Pan
    Research Article Updated

    Ferroportin (Fpn) is a transporter that releases ferrous ion (Fe2+) from cells and is important for homeostasis of iron in circulation. Export of one Fe2+ by Fpn is coupled to import of two H+ to maintain charge balance. Here, we show that human Fpn (HsFpn) binds to and mediates Ca2+ transport. We determine the structure of Ca2+-bound HsFpn and identify a single Ca2+ binding site distinct from the Fe2+ binding sites. Further studies validate the Ca2+ binding site and show that Ca2+ transport is not coupled to transport of another ion. In addition, Ca2+ transport is significantly inhibited in the presence of Fe2+ but not vice versa. Function of Fpn as a Ca2+ uniporter may allow regulation of iron homeostasis by Ca2+.