Some aspects of intercellular Ca wave spread are similar to

Some aspects of intercellular Ca2+ wave spread are similar to the phenomenon of spreading depression and associated with migraine headache [57]. These depolarization waves, followed by electrical inhibition, are evoked by transient hypoxia and other types of PF-CBP1 hydrochloride injury and spread slowly across the cortex and other brain regions. Spreading depression is similar to Ca2+ wave spread among astrocytes with regard to velocity and sensitivity to GJ/Panx1 inhibitors [58], although the mechanism is generally believed to involve elevated K+ and glutamate release, rather than ATP [59]. Both GJs [60] and Panx1 channels [61] have been implicated in migraine headache and spreading depression, and a putative GJ channel blocker (tonabersat) was initially touted for migraine relief [62], although clinical trials were unsuccessful and its effects on coupling have been questioned (see [63], [64]). A model conceptually similar to spreading depression entitled the ‘ignition theory' has been proposed to explain allodynia [65], [4], where a self-sustaining mechanism (positive feedback) must exist in sensory ganglia to maintain paroxysmal pain. This mechanism is envisioned to include two elements: “electrical cross talk” and “crossed after discharge”, which requires chemical communication between neurons. Although this theory was applied to trigeminal neuralgia, it can be generalized to other pain types. We propose specific elements for this model: The electrical cross talk likely involves the GJs found in SGCs and neurons in pain models, and the after discharge correlates with the augmented release of ATP, one major pathway of which is Panx1, and increased sensitivity of purinergic receptors. The ignition theory did not include SGCs, which appear to be key players in this scheme.
Conclusions
Conflict of interest statement
Introduction An essential aspect of the physiological regulation of vascular resistance and blood flow control is the signal transfer between endothelial cells (EC) and vascular smooth muscle cells (VSMC) [,2]. This is enabled by the formation of myoendothelial gap junctions (MEGJ) [3], which are formed within specialized actin-based cell protrusions (either from EC, VSMC or both), making direct contacts through the fenestrated internal elastic lamina (IEL) [4, 5, 6]. The formation of functional gap junction (GJ) channels requires the assembly of six connexin (Cx) proteins into hemichannels, their insertion into the membrane and the docking to another hemichannel in the adjacent cell [7,8]. The channel-forming N-terminal part is highly conserved between the members of the Cx family, whereas the cytoplasmic C-terminal tail varies in length and composition and is the main site of regulation []. As EC express mainly Cx37, Cx40 and Cx43 [10,11] and VSMC Cx43 and Cx45 [12,13], several combinations are possible, but not all form functional GJ channels with each other: MEGJ may be homotypic: Cx43/Cx43 [14,15] or heterotypic: Cx37/Cx43 [14,16,17], Cx37/Cx45 [14], Cx43/45 [14,18,19], Cx40/Cx43 [6,15,20] or Cx40/Cx45 [14,21,22].
Composition of MEGJ MEGJ are located not only between projections of EC and VSMC (see Figure 1) but also between endothelial projections and the surface of VSMC [23,24]. The source of these projections seems to vary depending on the vessel type. In small skeletal and mesenteric arteries, MEGJ are located at the interface of EC projections and the surface of VSMC, whereas in large arteries MEGJ are also at the interface of adjoining projections built by both cell types (EC and VSMC) [3,23,25]. The combination of Cx in MEGJ varies between the individual species and the vessel type. MEGJ composed of Cx37/Cx40 are found in rat basilar arteries [26,27], whereas mainly Cx40/Cx43 MEGJ have been detected within actin bridges of mouse cremaster arterioles [6]. The ability to form Cx40/Cx43 channels is a matter of controversy. Functional GJ of Cx40/Cx43 have been demonstrated in vitro [15,20], but several groups have reported a lack of coupling because of its inability to dock [14,21,22,28]. Homotypic MEGJ have been shown to be important in thoracodorsal arteries of mice where mainly Cx43 is expressed at MEGJ [29]. Our own findings in small arteries (lower saphenous arteries of mice) suggest a fundamental role for MEGJ composed of Cx37/Cx43 [16]. The in vivo existence of MEGJ containing Cx45 cannot be excluded per se, as studies with transfected HeLa cells have demonstrated functional coupling of mouse or human Cx37/Cx45, rat/mouse or human Cx43/Cx45 and mouse Cx40/Cx45 GJ [14,22,30], while their human homologues could not form Cx40/Cx45 GJ [18,30]. The difference in GJ coupling of human Cx40/Cx45 compared to their mouse homologues could be due to sequence discrepancies of Cx40, whereas Cx45 homologues are nearly identical in mouse and human (>97% similarity). Indeed, a D55N mutation of human Cx40 rescues the docking and formation of heterotypic human Cx40/Cx45 [30].