HA Receptors

Integrins themselves are found on nearly all cells and mediate several physiological responses, such as cell-cell and cell-matrix interactions. Three families of integrins, each family with a common beta subunit in combination with distinct alpha subunits, have been recognized. The beta 1 family, also called very late lymphocyte-activation antigen or VLA, has receptors mediating extracellular matrix interactions with molecules such as collagen, laminin, and fibronectin. Naturally, platelets contain many of the receptors of the beta 1 family. 

The beta 2 family has receptors on leukocytes (also called LeuCAM) and mediates inflammatory and immune recognition functions. 

HA receptors are classified into 4 subtypes Hi, H2, H3, and H4 (Hill et al, 1997). All four HA receptor types are metabotropic receptors and belong to the superfamily of G-protein coupled receptors. Ionotropic HA receptors are found in invertebrates (Hardie, 1989 Gisselmann et al., 2002) but are absent from vertebrates (Haas Panula, 2003). Of the four HA receptors, only the Hi, H2, and H3 receptors are found in brain. The recently discovered H4 receptor is predominantly present on leukocytes and may have a critical role in the immune system (Nguyen et al., 2001 Bakker, 2004 Haas 8i Panula, 2003). 

The H2 receptor is the second class of HA receptors. This is another G-protein-coupled receptor but, unlike the Hi receptor, the H2 receptor is coupled to adenylyl cyclase via the GTP-binding Gs protein (Hill et ah, 1997). Encoded by an intronless gene and located on human chromosome 5, the H2 receptor is made up of c. 358 amino acids (Gantz et ah, 1991 Traiffort et ah, 1995). Activation of the H2 receptor causes an accumulation of cAMP and activation of protein kinase A that eventually leads to the activation of cyclic-AMP-response element (CRE)-binding protein (CREB) (Hill et ah, 1997). In neurons, the H2 receptor mediates its excitatory effects by blocking the Ca2+-dependent K+ channel (Haas Konnerth, 1983). 

If compared to the neuro muscular junction at skeletal muscle the diffusion distance for the transmitter in the synaptic cleft is much longer. Furthermore, the membrane of the target cell is not specialized at the site of the junction but has receptors at the whole surface. In contrast to the all or nothing response of the skeletal muscle cell, the response of the sympathetic target cell to the transmitter is concentration-proportional, or graduated. 

Hormone Effect of HA Postsynaptic HA receptor Mediators and (Site of action of HA) Physiological actions involving HA... 

The HA H3 receptor is further localized on the histaminergic nerve terminals in the brains of rats.40 41-4346 Of the three subclasses of HA receptor that have been identified in the brain, the Hi and H2 receptors are thought to be exclusively post-synaptic.4649 The H3 receptor found on the histaminergic nerve terminal was defined as an autoreceptor and is thus a HA receptor subtype that is uniquely positioned to regulate the amount of HA synthesized and released from the HA neurons.45- 60 Moreover, the presence of H3 receptors on several non-histaminergic nerve terminals (heteroreceptors) has now been further established. Modulation of neurotransmitter... 

Chemokines are redundant in their action on target cells. Furthermore, a given leukocyte population usually has receptors for and responds to different molecules (Table 3). For example, macrophages respond to the widest range of chemokines... 

A vertebrate homologue of the cell cycle control protein CDC37 was recently cloned and found to be an hyaladherin,62 as was a protein that copurified with the splicing factor SF2.63 An intracellular form of the HA receptor RHAMM was demonstrated to regulate erk kinase activity. Changes in function of these intracellular, depending on whether or not they have HA molecules attached, confers another layer of complexity dependent on intracellular hyaluronidase enzymes. 

The hyaluronasome, because of its ability to respond to extracellular events as well as to the intracellular metabolic state of the cell may contain HA receptors such as RHAMM and CD44, HA synthase enzymes, the hyaluronidases, hyaluronidase inhibitors,247,248 the /i-cxoglycosidascs, and HA-binding proteins such as HABP1.249... 

Antihistamines differ primarily in terms of their potency, selectivity of action, and side effects. The newer second-generation Hj blockers, loratadine and fexofenadine, for example, are more specific for Ha receptor antagonism than the older generation, which can also block cholinergic and muscarinic receptors. In addition, the... 

Histamine Hi and Ha receptor antagonists may be used in addition to corticosteroids, but opinion is divided... 

The existence of HA layer covering certain cells (e.g. chondrocytes and epithelial cells) is known since a long time [77] and has attracted considerable research interest because this coat protects the cells against lymphocytes and viruses. This is maybe the reason why Streptococci strains represent important sources of HA These cells are protected from macrophages by an envelope of HA. Interestingly, it could also be shown that the formation of HA coats can be induced in cells with HA receptors on their surface by the simple addition of exogenous HA [78]. 

Preliminary evidence for the existence of such an organelle comes from a variety of sources. Treatment of cells with low concentrations of hyaluronidase stimulates anomalous levels of HA synthesis, suggesting that some feedback mechanisms exist that instruct the cells in the status of HA metabolism [102,103]. Treating cells with even higher concentrations of hyaluronidase stimulates levels of expression of the predominant HA receptor, CD44 [104,105]. 

Thus, there appears to be an interlocking directorate with dynamic reciprocity for the various components of HA deposition that responds to the immediate needs of the cell. A tightly associated complex, termed the hyaluronasome, that contains HA receptors, the HA synthases, hyaluronidases, their respective inhibitors, exo- -glycosidases, as well as a spectrum of HA-binding proteins may constitute such an organelle. 

The primary pathway for HA turnover occurs at the tissue and whole organism level, and accounts for 85% of total catabolism. HA is released from tissue matrix, drained mostly into the lymphatics, with some residual into the bloodstream, with final steps of elimination occurring in liver, kidney, and possibly spleen. This pathway involves unique receptors such as HA Receptor for... 

Endocytosis (HARE) [169] and Lymphatic Vessel Endothelial HA receptor (LYVE-1) [170]. When the hepatic or renal arteries are ligated, levels of circulating HA rise immediately, underscoring the importance of this pathway [171]. 

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