Modulatory action of RFamide‐related peptides on acid‐sensing ionic channels is pH dependent: the role of arginine

Abstract

Acid-sensing ionic channels (ASICs) are involved in such functions of the sensory nervous system as mechanoreception, nociception and perception of acid taste. Phe-Met-Arg-Phe amiderelated (FMRFa-related) peptides in lM concentrations slow down the rate of ASICs desensitization. Here we report that this effect is strongly pH dependent: the lower the pH used to activate ASICs, the larger is the modulatory effect of Arg-Phe amide-related (RFarelated) peptides. Pre-application of the peptides results in a change to the desensitization kinetics of the ASICs-operated current from monoexponential to biexponential: the fast component retains the control kinetics, whereas the slow one is induced by the peptide. The lower the pH, the larger is the slow component, whereas there is practically no modulation at pH 6.6. PheMet-Val-Phe amide (FMVFa), which has neutral valine instead of arginine, similarly modulates the kinetics of ASICs, but does not reveal pH dependence of this action. Thus, positively charged arginine regulates the access of the RFa-related peptides to the modulatory site. We suggest that the pH dependence of the modulatory action of RFa-related peptides can be associated with the interaction of a positively charged arginine with histidine residues in the molecule of ASIC. Keywords: acid-sensing ionic channels, pH dependence, protonactivated current, Arg-Phe amide-peptides, sensory neurons. The acid-sensing ionic channels, ASICs, belonging to the epithelial sodium channel (ENaC)/degenerin family (Waldmann and Lazdunski 1998) are proven to be functionally important both in the CNS and at the periphery. The time course of the ASICs desensitization in native sensory neurons is variable (Krishtal and Pidoplichko 1981) and depends on the subtypes of ASICs expressed (Waldmann and Lazdunski 1998). Selective elimination of various subtypes of ASICs affects a variety of sensory functions such as mechanoreception, pain sensitivity and perception of acid taste (Price et al. 2000(Price et al. , 2001Wemmie et al. 2002). Except for protons, the endogenous ligands of ASICs remain unknown and it is unclear how these channels contribute to sensory processing within the physiological range of pH. The findings of different authors indicate that mollusc-derived peptide, FMRFamide (FMRFa) and its analogs efficiently slow down the rate of desensitization of ASICs in dorsal root ganglion (DRG) neurons (Askwith et al. 2000;Xie et al. 2002Xie et al. , 2003 and in hippocampal neurons (Askwith et al. 2004). FMRFa increases both peak value and late component of the response to acids in Purkinje neurons (Allen and Attwell 2002). These observations are confirmed for some of the mammalian endogenous RFa related peptides (Catarsi et al. 2001;Deval et al. 2003;Xie et al. 2003). To access the structure-activity relationship in this ligand group, we tested the action of several RFa-related peptides on the kinetic parameters of ASICs in the sensory neurons from dorsal root ganglia (DRG) and trigeminal ganglia. Here we report that the ...

Peptide-gated ion channels and the simple nervous system of Hydra

“…As mentioned before, HyNaCs are indeed not activated by H + . However, ASICs are not activated by neuropeptides, but RFamide neuropeptides, including FMRFamide, can modulate the ASIC current (Askwith et al, 2000;Catarsi et al, 2001;Deval et al, 2003;Xie et al, 2003;Ostrovskaya et al, 2004;Chen et al, 2006;Sherwood and Askwith, 2008;Sherwood and Askwith, 2009). It is believed that neuropeptides directly bind to ASICs to modulate the H + -activated current.…”

Exploration of the Peptide Recognition of an Amiloride-sensitive FMRFamide Peptide-gated Sodium Channel

“…5A). The electronegative TNB group would interact with the positively charged arginine of FMRFamide, therefore altering the affinity between FMRFamide and the mutated channel (30,31). Indeed, after the application of DTNB (1 mM) to I160C, 100 M FMRFamide hardly evoked a detectable inward current of the channel.…”

On the Putative Binding Site of RFamide‐Family Neuropeptides from the Western Atlantic Clam Sunray Venus and Cephalopods on Acid‐Sensing Ion Channels. An Automated Docking and Molecular‐Dynamics Study with hASIC1a Homology Model

“…Also, the binding site has been suggested [13] to lie in what is now known to be the cASIC1 wrist [14], which is rich in titrable histidine residues. This proposal [13] relied on the established role of FMRFa arginine in modulating the currents [11]. Albeit on a vague basis, such a proposal for the binding site [13] stimulated us to investigate the problem theoretically.…”

“…It has been argued that it is the arginine residue of these peptides that mainly modulates the bioactivity [13]. Also, the binding site has been suggested [13] to lie in what is now known to be the cASIC1 wrist [14], which is rich in titrable histidine residues.…”

“…This proposal [13] relied on the established role of FMRFa arginine in modulating the currents [11]. Albeit on a vague basis, such a proposal for the binding site [13] stimulated us to investigate the problem theoretically. The main scope was to contribute to the clarification of the role of these peptides in marine invertebrates, still a most obscure matter [15].…”