Exchangeability inhibitory activity

Table 9.1 Na/H exchange inhibitory activities and selected features of 20 compounds.

At the N-terminal end of the f loop, near the membrane lipid interface, there is an autoinhibitory domain, rich in both basic and hydrophobic residues and consisting of a 20-aminoacid sequence (219-238). This aminoacid sequence, named exchange inhibitory peptide (XDP), is involved in NCX activity regulation. 

Modifications at the terminal guanidine nitrogen greatly enhance inhibitory activity of the epithelium Na+ channel. They markedly decrease that of the Na+/H+ exchanger. 

The intracellular pH can also regulate the exchanger. [H+] strongly inhibits NCX activity under steady-state conditions, in fact, reduction in [pH] values, as little as 0.4, can induce a 90% inhibition of NCX activity. Such inhibitory action depends on the presence of intracellular Na+ ions, hence, the action exerted by H+ ions is pathophysiologically relevant with regards to brain and heart ischemia. 

Na+/Ca2+ Exchangers. Figure 5 Chemical structures of amiloride derivatives and their IC50 on NCX and NHX activity. Chemical structure of the two classes of amiloride derivatives and their inhibitory concentrations on NCX and Na+/H+ exchanger activity (Reproduced from Annunziato L, Pignataro G, Di Renzo GF (2004) Pharmacol Rev 56 633-654). 

Figure 6.3. Mechanism of action of heterotrimeric G-proteins. Upon receptor occupancy, the Ga-subunit binds GTP in exchange for GDP, and then moves in the membrane until it encounters its target enzyme, shown here as adenylate cyclase (alternatively, a phospholipase). The activated target enzyme then becomes functional. Inherent GTPase activity within the a-subunit then hydrolyses bound GTP to GDP, and the a-subunit dissociates from its target enzyme (which becomes inactive) and rebinds the / - and ysubunits. Upon continued receptor occupancy, further catalytic cycles of GTP exchange and target enzyme activation may occur. The scheme shown is for a stimulatory G-protein (Got,), but similar sequences of events occur with inhibitory G-proteins (Gcx,) except that the interaction of the a-subunit with adenylate cyclase will result in its inhibition. The sites of action of pertussis and cholera toxins are shown.

Neurotransmitters can either excite or inhibit the activity of a cell with which they are in contact. When an excitatory transmitter such as acetylcholine, or an inhibitory transmitter such as GABA, is released from a nerve terminal it diffuses across the synaptic cleft to the postsynaptic membrane, where it activates the receptor site. Some receptors, such as the nicotinic receptor, are directly linked to sodium ion channels, so that when acetylcholine stimulates the nicotinic receptor, the ion channel opens to allow an exchange of sodium and potassium ions across the nerve membrane. Such receptors are called ionotropic receptors. 

Prostanoid receptors and their signaling pathways. fMLP, formylated MetLeuPhe, a small peptide receptor PLC-3, phospholipase C-3. All of the receptors shown are of the 7-transmembrane, G-protein coupled type. The terms "relaxant," "contractile," and "inhibitory" refer to the phylogenetic characterization of their primary effects. AII EP3 isoforms couple through G but some can also activate Gs or G12/13 pathways. RhoGEF, rho guanine nucleotide exchange factor. See text for additional details. 

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