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. Author manuscript; available in PMC: 2013 Jul 28.
Published in final edited form as: Trends Cardiovasc Med. 2012 Jul 28;22(3):68–72. doi: 10.1016/j.tcm.2012.06.014

Pannexin 1 in the regulation of vascular tone

Marie Billaud 1, Joanna K Sandilos 3, Brant E Isakson 1,2,*
PMCID: PMC3455115  NIHMSID: NIHMS390804  PMID: 22841835

Abstract

Pannexins are a recently discovered protein family, with the isoform Panx1 ubiquitously expressed and therefore extensively studied. Panx1 proteins form membrane channels known to release purines such as ATP. Because ATP and more generally purinergic signaling plays an important role in the vasculature, it became evident that Panx1 could have a key role in vascular functions. This article review deals with recent findings on the pivotal role of Panx1 in smooth muscle cells in the contraction of arteries as well as recent insights in Panx1 channel regulation.

Introduction

Pannexins were described for the first time in 2000 as an orthologous gene of the invertebrate gap junction protein innexins (Panchin et al. 2000). Pannexins are present in virtually all tissues including the vasculature (Lohman et al. 2012b) and have been functionally characterized as plasma membrane channels that release purines such as ATP (Bao et al. 2004; Huang et al. 2007b; Lohman et al. 2012a; Ransford et al. 2009). With the central role of purinergic signaling in the vasculature where it regulates vascular tone (Burnstock 2007; Kauffenstein et al. 2009; Kauffenstein et al. 2010), the potential contribution of pannexins in this function has become evident.

What do we know about pannexins?

The pannexin family consists of three members: pannexin 1 (Panx1), pannexin 2 (Panx2) and pannexin 3 (Panx3) with a sequence similarity of approximately 50–60 %. Out of the three isoforms, Panx1 is ubiquitously expressed in mammalian tissues whereas Panx2 and Panx3 expression is more restricted to specific tissues. Therefore, in the past decade, Panx1 has garnered the most attention and massive effort has been put in investigating the functional properties as well as physiological function of Panx1 channels.

Structurally, the hydrophobicity profile reveals that Panx1 contains four transmembrane domains, an intracellular loop, two extracellular loops and intracellular amino and carboxyl termini (Baranova et al. 2004; Panchin et al. 2000; Yen and Saier 2007). Interestingly, the hydrophobicity profile of Panx1 also demonstrates a fifth hydrophobic domain in the carboxyl terminus sequence (Figure 1). A substituted cysteine accessibility method (SCAM) analysis recently demonstrated that the carboxyl terminus of Panx1 is associated with the pore formed by the assembly of six Panx1 proteins (Wang and Dahl 2010). Additionally, it was recently demonstrated that the Panx1 carboxyl terminus can inhibit channel activity in trans and its removal from the channel pore is essential to open the channel (Sandilos et al. 2012). Therefore, the presence of the fifth hydrophobic domain in Panx1 carboxyl terminus could be correlated with the role of the carboxyl terminus as a pore blocker and/or with insertion into the plasma membrane, but the exact role of this fifth hydrophobic domain remains to be clarified.

Figure 1. Association between Panx1 and the α1D-adrenergic receptor.

Figure 1

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Illustration demonstrates the effects of phenylephrine (PE, or norepinephrine; purple triangle) inducing activation of the α1D-adrenergic receptor (α1D-AR; blue) and subsequent effect on Panx1 channel (orange) opening and purine (e.g., ATP; green) release as demonstrated by us (Billaud et al. 2011). Images on right are cut away topography of the images on the left. Although we have shown by co-immunoprecipitation on intact arteries that the two proteins can be pulled out by one another, the exact interaction between α1D adrenergic receptor and Panx1 is unknown (represented by the question mark). Lastly, recent evidence indicates the carboxyl terminus (C) of Panx1 functions as a blocker of the channel pore maintaining the Panx1 channel in a closed state (Sandilos et al. 2012).

Functionally, although early work done in overexpression systems suggested that Panx1 could form intercellular gap junctions, this has not been supported in any native context (Baranova et al. 2004; Bruzzone et al. 2003; Huang et al. 2007a; Lai et al. 2007). Instead, Panx1 have been identified as large-pore membrane channels formed by the assembly of six Panx1 proteins (Boassa et al. 2007; Ma et al. 2009; Pelegrin and Surprenant 2006). The channels formed by Panx1 are theoretically permeable to molecules up to 1 kDa in size and have been shown to provide a conduit for release of purines such as ATP (Bao et al. 2004; Huang et al. 2007b; Ransford et al. 2009). The selectivity of the channels has yet to be fully characterized.

To date, the majority of the functional studies accomplished on pannexins were focused on the immune system and on the central nervous system where Panx1 is abundantly expressed (Bruzzone et al. 2003; Chekeni et al. 2010; Kanneganti et al. 2007; Pelegrin and Surprenant 2006; Ray et al. 2006; Schenk et al. 2008; Thompson and Macvicar 2008; Vogt et al. 2005). In the central nervous system, Panx1 plays a role in paracrine communication between astrocytes and adjacent cells and these channels have been implicated in ischemia-induced neuronal death and epileptic seizures (Santiago et al. 2011; Scemes and Spray 2012; Scemes et al. 2007; Silverman et al. 2009). In the immune system, Panx1 channels are involved in the recruitment of the inflammosome (Kanneganti et al. 2007) and the release of the pro-inflammatory cytokine interleukin-1β from macrophages after stimulation of P2X7 receptors by ATP (Pelegrin and Surprenant 2006). In addition, Panx1 plays a major role in cell clearance process where Panx1 expressed at the plasma membrane of dying cells releases ATP as a “find-me” signal, further targeting the recruitment of phagocytes (Chekeni et al. 2010).

Panx1 regulation

Given that Panx1 channels are characterized by a high conductance, these channels must be very tightly regulated; otherwise electrochemical gradients would quickly dissipate resulting in the rapid demise of the cell (Bao et al. 2004). Although this area of research on pannexins is currently ongoing in many laboratories, some examples of Panx1 regulation currently exist in the literature.

There is no evidence to date that Panx1 channels can be activated via post translational modification such as phosphorylation (Penuela et al. 2007). However given the vast number of cysteines, tyrosines and serines present in Panx1, this type of regulation will need to be examined more closely. It has been demonstrated that Panx1 channels can be activated by several mechanisms such as mechanical stretch in oocytes (Bao et al. 2004), increase of extracellular potassium concentration in primary neurons and astrocytes (Silverman et al. 2009), increase of intracellular calcium concentration in oocytes (Locovei et al. 2006), membrane depolarization in oocytes and HEK293 cells (Bao et al. 2004; Ma et al. 2009) or cleavage of the carboxyl terminus by caspase 3 in Jurkat cells (Chekeni et al. 2010). Conversely, Panx1 channels can be inhibited by ATP itself, providing a mechanism for negative feedback regulation (Qiu and Dahl 2009).

A growing body of work has now established mechanisms of receptor-mediated Panx1 channel modulation. One of the first Panx1 signaling partners identified was the purinergic class of receptors P2X, including P2X7 receptor and this protein complex is now known to take part in a wide variety of cellular processes (Iglesias et al. 2008; Locovei et al. 2007; Pelegrin 2008). There has been some evidence for other purinergic receptors interacting with Panx1, specifically P2X family members P2X1, P2X4, and P2X5 during T-cell activation (Woehrle et al. 2010a; Woehrle et al. 2010b). Additionally, the receptors P2X7, as well as P2X2, P2X3, and P2X4 have been shown to co-immunoprecipitate with Panx1 in rat pituitary cells (Li et al. 2011). While P2Y receptors are generally thought to act downstream of Panx1, one study provides evidence for P2Y1 and P2Y2 mediated activation of Panx1 (Locovei et al. 2006). Moreover, Panx1 can be activated upon stimulation of the NMDA receptor in the hippocampus and a deregulation of this process has been proposed to play a role in epilepsy (Thompson and Macvicar 2008). Very recently, a group demonstrated that PAR-1 receptor stimulation via thrombin can induce ATP release from human umbilical vein endothelial cells which is mediated by Panx1 channels (Godecke et al. 2012).

Panx1 in α1 adrenergic signaling

We were particularly interested in pannexin channels because they provide a conduit for purines, such as ATP, which are potent regulators of vascular tone and their role in the regulation of blood pressure is therefore strongly speculated (Burnstock 2007; Burnstock 2009; Hopwood and Burnstock 1987; Kauffenstein et al. 2010; Lohman et al. 2012a). To date, pannexins have been poorly investigated in the vasculature despite the central role of ATP in the regulation of vascular functions and the high expression of purinergic receptors in the vasculature (Burnstock 2009; Houston et al. 1987; Kennedy et al. 1985; Lohman et al. 2012a). We thus decided to examine pannexin expression in the vasculature and demonstrated that Panx1 is ubiquitously expressed in the systemic arterial wall, both in endothelial cells and smooth muscle cells (Lohman et al. 2012b). Interestingly, Panx1 expression was higher in smooth muscle cells from smaller arteries as compared to larger arteries where Panx1 expression was restricted to the endothelial cells (Lohman et al. 2012b). Because it is the small arteries that have a more direct role in peripheral resistance and thus in blood pressure, this led us to hypothesize that smooth muscle Panx1 may be involved in the regulation of peripheral resistance.

Peripheral resistance is highly regulated by the sympathetic nervous system, where neuronal terminations target the smooth muscle cells (Jackson et al. 2008; Tanoue et al. 2002). The α1D-adrenergic receptor expressed on the smooth muscle mediates the functional effect of catecholamines such as epinephrine and norepinephrine that are released from the sympathetic nerves (Billaud et al. 2011; Jackson et al. 2008; Tanoue et al. 2002).

Using different techniques including western blotting, immunofluorescence and immunogold labeling coupled to transmission and scanning electron microscopy, we demonstrated the presence of Panx1 at the plasma membrane of the smooth muscle cells composing the thoracodorsal arterial wall (Billaud et al. 2011). In order to identify the role of Panx1 in the regulation of vascular tone, we measured the contractile response of pressurized thoracodorsal arteries in response to cumulative concentrations of phenylephrine, an α1-adrenergic receptor agonist, in the presence of several Panx1 pharmacological inhibitors (Billaud et al. 2011). Using two different concentrations of these inhibitors (probenecid 0.5 mM and 2 mM, mefloquine 10 and 20 μM and 10Panx1 200 and 300 μM), we were able to significantly reduce the ability of thoracodorsal arteries to constrict to phenylephrine (Billaud et al. 2011). Because the pharmacology of pannexins is similar to connexins and is inherently non-specific, and because some of the drugs we used (probenecid and mefloquine in particular) can potentially inhibit other targets, we decided to use molecular biology to modulate Panx1 expression specifically in the smooth muscle cells. Using electroporation to transfect the smooth muscle cells of intact thoracodorsal arteries with either siRNA targeting Panx1 or a plasmid containing a Panx1-GFP construct, we were able to decrease or increase the amount of Panx1 in the smooth muscle respectively (Billaud et al. 2011). After cannulating the vessels where Panx1 expression was increased in the smooth muscle, we were able to measure a higher constriction to phenylephrine whereas the constriction to phenylephrine was reduced in vessels where Panx1 expression was decreased (Billaud et al. 2011). Altogether, these results demonstrated that Panx1 participates in the phenylephrine constriction and, most importantly, that the degree of constriction to phenylephrine appeared to correlate with the amount of Panx1 in the smooth muscle cells (Billaud et al. 2011).

Because Panx1 channels are known to release purines such as ATP, we further investigated the role of ATP itself in the phenylephrine response. First, we treated pressurized thoracodorsal arteries with an enzyme that degrades extracellular ATP, apyrase, which led to a significant reduction of phenylephrine response (Billaud et al. 2011). Then, we demonstrated on cultured vascular smooth muscle cells that ATP was released via Panx1 upon stimulation with phenylephrine (Billaud et al. 2011). Lastly, we used two pharmacological blockers of purinergic receptors, suramin and reactive-blue 2, to evaluate the role of purinergic signaling in the phenylephrine response. Our results suggested that the P2Y family of purinergic receptors is involved in the phenylephrine response (Billaud et al. 2011). However, the exact isoform remains to be determined.

None of the pharmacological blockers used to inhibit Panx1 or the purinergic receptors or used to degrade ATP, had an effect on the constriction in response to 40 mM KCl (Billaud et al. 2011). This led us to hypothesize that Panx1 and ATP could be involved specifically in the phenylephrine response mediated by the α1D adrenergic receptor. We thus decided to investigate the relationship between Panx1 channels and the α1D adrenergic receptors. Using double immunofluorescence, double immunogold labeling as well as co-immunoprecipitation, our results show that both proteins co-localize and co-immunoprecipitate (Billaud et al. 2011). These results are tantalizing, but require further investigation as to their interaction.

Altogether, our results on cannulated vessels show that both Panx1 and extracellular ATP are involved in phenylephrine response. Furthermore, the data appear to indicate that Panx1 and α1D-adrenergic receptors are likely part of the same protein complex at the membrane of arterial smooth muscle cells.

Perspectives

Based on our work, we hypothesized a key role for smooth muscle Panx1 in α1D-adrenergic receptor-mediated response in thoracodorsal arteries. Because Panx1 is expressed in the smooth muscle of small arteries (e.g., abdominal arteries, skeletal muscle arterioles and cremasteric arterioles (Lohman et al. 2012b)) and because the phenylephrine response is mediated by the α1D adrenergic receptor in several vascular beds (e.g.: cremasteric arterioles and mesenteric arteries (Jackson et al. 2008; Tanoue et al. 2002)) we believe that the contribution of Panx1 in α1D-adrenergic receptor-mediated constriction can be found throughout the systemic circulation. Furthermore, although our research is currently focused on the role of Panx1 in the smooth muscle cells, because Panx1 and multiple isoforms of purinergic receptors are highly expressed in endothelial cells (Burnstock 2009; Lohman et al. 2012b), it is very likely that Panx1 could participate in endothelial specific vascular functions.

Our results demonstrate that Panx1 and the α1D-adrenergic receptor colocalize and co-immunoprecipitate, which suggests that the two proteins are in a functional complex and/or that they directly interact. The α1D-adrenergic receptor is coupled to a Gq protein, therefore the opening of Panx1 channels could be directly or indirectly activated by the α or the βγ subunits upon stimulation of the receptor (Figure 1). The activation of Panx1 by adrenergic receptor has also recently been demonstrated in cell culture (Sumi et al, 2010), highlighting our ex vivo results. On the other hand, adrenergic receptors are known to directly interact with protein partners (Cotecchia et al. 2012). Regardless, the exact nature of the interaction between Panx1 channels and the α1D-adrenergic receptor will give new insights on the regulation of Panx1 activity, which is a current topic of investigation in the field. Furthermore, because we demonstrated a contribution of P2Y receptors in phenylephrine response, it could be hypothesized that Panx1 and the α1D-adrenergic receptors as well as a P2Y receptor are part of a larger protein complex.

The discovery of the role of Panx1 channel in phenylephrine response opens new perspectives on the α1D-adrenergic receptor-mediated response but also reinforces the role of ATP in the regulation of vascular tone. Because the α1D adrenergic receptor is essential in the regulation of small arterial tone and in blood pressure through its binding to noradrenaline (Jackson et al. 2008; Tanoue et al. 2002), the participation of Panx1 channels in phenylephrine response now suggests a role for Panx1 in these physiological functions. Pathologically, the implication of Panx1 in cardiovascular disease is currently unknown, but our work raises the possibility that Panx1 could be involved in blood pressure regulation, which could make it a molecular component to the development of hypertension.

In conclusion, the identification of the exact mechanism by which the α1D-adrenergic receptor opens Panx1 channels to release ATP could provide new insights on the regulation of peripheral resistance and blood pressure by the sympathetic nervous system. Conceptually, Panx1 could be considered as a potential therapeutic target, however further studies of Panx1 in the vasculature are required to push this idea forward.

Acknowledgments

This work was supported by National Institutes of Health grants HL088554 and HL107963 (B.E.I.), American Heart Association Scientist Development Grant (B.E.I.) and an American Heart Association postdoctoral fellowship (M.B.).

Footnotes

Conflict of Interest

None.

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