Frontiers | Inositol 1,4,5-Trisphosphate Receptors in Hypertension | Physiology
This will depend largely on the activation state of the Ins(1,4,5)P3 receptor and the Calcium and inositol 1,4,5- trisphosphate receptors: a complex relationship. Sorrentino V () The ryanodine receptor family of intracellular calcium release Calcium and inositol 1,4,5-trisphosphate receptors: a complex relationship. Ca2 release induced by inositol 1,4,5-trisphosphate is a steadystate Luminal Ca2 controls the activation of the Ins(1,4,5)P3 receptor by cytosolic Ca2. Inhibition of inositol trisphosphate-induced calcium release by caffeine is prevented Structure-function relationships of the mouse inositol 1,4,5- trisphosphate receptor.
The type II InsP3 receptor was not expressed in detectable amounts. Acetylcholine AChatropine, U, heparin average molecular weightde-N-sulfated heparin, trypsin, and sulforhodamine Texas red were obtained from Sigma Chemical St.
All other chemicals were of the highest quality commercially available. Antibodies The type I InsP3 receptor was labeled using affinity-purified rabbit polyclonal antibody T, directed against the 19 C-terminal amino acids of the mouse type I InsP3 receptor.
Preparation of Isolated Ciliary Epithelium Isolated ciliary bilayer epithelium was prepared as described previously, 22 23 with slight modification. Briefly, rabbits were anesthetized with an intramuscular injection of ketamine hydrochloride and xylazine, then euthanatized by intravenous injection of pentobarbital sodium and phenytoin sodium.
The eyes were enucleated promptly, then the anterior segments were isolated after careful removal of the lens. From the isolated anterior segment of the eye, ciliary processes were separated from the iris and cut into 10 to 20 strips, each 2 to 3 mm in length.
Confocal Immunofluorescence Histochemistry Sections of rabbit ciliary epithelia were labeled with isoform-specific antibodies to determine the subcellular distributions of the types I, II, and III InsP3 receptors. Specimens were colabeled with rhodamine-phalloidin Molecular Probes because this stain facilitates identification of the apical and basolateral poles of epithelial cells.
To ensure specificity of InsP3 receptor staining, images were obtained using confocal machine settings i. This approach eliminated bleed-through of FITC fluorescence into the rhodamine channel. An argon laser was used to excite the dye at nm, and emission signals above nm were collected. Neither autofluorescence nor other background signals were detectable at the machine settings used, and there was no change in size, shape, or location of cells during the experiments.
In this mode, fluorescence is determined at each point along a single line across the image, rather than at each point across the entire image. A series Eppendorf micromanipulator was used for positioning, and an Eppendorf series microinjector was used for pressure-microinjections. Chronic hypertension predisposes nearly 1.
A number of factors are known to increase the risk of high BP development including obesity, sedentary lifestyle, insulin resistance, high alcohol intake, high salt intake, smoking, and aging Carretero and Oparil, ; Gates et al. The development of essential hypertension involves multiple physiological mechanisms including cardiac output, peripheral resistance, renin—angiotensin—aldosterone system, autonomic nervous system, and vasoactive substances such as endothelin, bradykinin, natriuretic peptides, and others Beevers et al.
The etiology of hypertension is complex and results from the interaction of multiple genetic, neuronal, hormonal, environmental factors, and aging-associated diseases Garbers and Dubois, ; Oparil et al.
In fact, with over 50 genes implicated in BP regulation, and other risk factors contributing to the pathogenesis of hypertension, it is rarely possible to determine the etiology of the disease. In fact, progressive aging implies endothelial dysfunction, loss of nitric oxide NO bioavailability, impaired vasodilation, vascular remodeling, and increased arterial stiffness.
Regardless of its etiology, a hallmark of all cases of hypertension is an increased vascular resistance that leads to elevated BP. The major drop in hydrostatic pressure in the vascular tree occurs at the level of resistance arteries.
Hence, peripheral resistance is typically a function of the diameter of resistance arteries which, in turn, is intricately linked to the contractility state vasomotor tone of vascular smooth muscle cells VSMCs Bosnjak, ; Hill et al.
Calcium and inositol 1,4,5-trisphosphate receptors: a complex relationship.
Indeed, it is these VSMCs in resistance arteries and arterioles that act as the main effectors in the continuous regulation of vascular resistance.
Furthermore, this tone represents the baseline on which various primary messengers such as neurotransmitters, endothelium-derived vasoactive molecules, local metabolites, or hormones converge and act to modulate constriction and dilatation.
Many membrane channels and receptors play a pivotal role in vasotone regulation. It is important to note that with sustained hypertension, vessels undergo progressive alteration characterized by inflammatory responses, VSMC growth and migration, extracellular matrix synthesis and degradation, endothelial dysfunction that increases vascular stiffness and resistance, and decreases vascular elasticity Shyu, ; Dharmashankar and Widlansky, ; Renna et al.
Remodeled vessels heavily contribute to the pathophysiology of vascular diseases such as atherosclerosis, and are subsequently at high risk of blockage or rupture that could damage and fail the supplied organ Renna et al. A summary of the proposed model is presented in Figure 1. IP3R is a tetramer, with each subunit encompassing an amino terminus, six transmembrane domains, and a carboxy terminal tail Michikawa et al.
The amino terminus contains an IP3-binding domain, a suppressor domain that inhibits IP3 binding, and a regulatory domain Yoshikawa et al.
Calcium and inositol 1,4,5-trisphosphate receptors: a complex relationship.
Within this regulatory domain, there is also a coupling motif that is important for physical interactions between IP3R and transient receptor potential canonical TRPC channels Tang et al.
The transmembrane and carboxy terminal domains are essential for tetramerization of IP3Rs Mignery and Sudhof, ; Sayers et al. This complexity is further compounded by the existence of many splice variants as well as the possibility of tetramerization Foskett et al. Although most cells express more than one IP3R subtype, the different subtypes exhibit some tissue-specific pattern of expression, with one subtype being expressed at a higher level than the others Vermassen et al.
Moreover, the different subtypes exhibit marked difference in their affinity for their ligand IP3 Ivanova et al. Likewise, ATP regulates all three isoforms but with a clear differential effect on each.
Moreover, while all three isoforms are targets for many kinases such as Akt, PKA, and MAP kinases, isoform-specific regulation by these kinases are markedly noticed. Vascular smooth muscle cells expresses all three subtypes, with IP3R1 being the predominant one in these cells Islam et al. Levels of these proteins are determined by a well-regulated balance between transcription and degradation.
Hydrogen peroxide Jak2 kinase, Herpud1, and vasopressin regulate levels of IP3R1 by modulating its degradation Sipma et al. Importantly, this localization may impart a functional effect. On the other hand, peripherally located SR allows their IP3Rs to be close enough to the PM for localized signaling to membrane proteins to be efficiently elicited Adebiyi et al.
The now released IRBIT can then modulate other targets such as transporters, channels as well as ribonucleotide reductase Ando et al.
Factors Affecting Vascular Tone: Alteration in Hypertension Under physiological conditions, individual components of the vascular system maintain a certain degree of spontaneous constriction constituting the vascular tone. This vascular property determines the dilatory capacity of the vascular bed and hence the organ, whereby a higher tone allows for a higher dilatory capacity as in the heart and skeletal muscles, and a lower tone leads to a limited dilatory capacity as in case of cerebral circulation Klabunde, Indeed, vascular tone results from the integration of several competing stimuli that modulate the contractile state of VSMC.
In isolated vessels, the myogenic response constitutes the fundamental form of vascular reactivity in response to increased intraluminal pressure Uchida and Bohr, Extrinsic influences converge to modulate this intrinsic contractility. The overall vascular tone is set as a net outcome of the interaction of endothelial inputs activated by sheer stress Koller et al.
The resultant level of constriction determines the extent of systemic vascular resistance and hence contributes to regulating BP, making the examination of alterations in vascular tone an attractive target in the study of hypertension. Significantly, studies showed substantial alterations in vascular tone in hypertension.