The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function

Abstract

The Cys-loop receptors constitute an important superfamily of LGICs (ligand-gated ion channels) comprising receptors for acetylcholine, 5-HT3 (5-hydroxytryptamine; 5-HT3 receptors), glycine and GABA (gamma-aminobutyric acid; GABAA receptors). A vast knowledge of the structure of the Cys-loop superfamily and its impact on channel function have been accrued over the last few years, leading to exciting new proposals on how ion channels open and close in response to agonist binding. Channel opening is initiated by the extracellular association of agonists to discrete binding pockets, leading to dramatic conformational changes, culminating in the opening of a central ion pore. The importance of channel structure is exemplified in the allosteric modulation of channel function by the binding of other molecules to distinct sites on the channel, which exerts an additional level of control on their function. The subsequent conformational changes (gating) lead to channel opening and ion transport. Following channel pore opening, ion selectivity is determined by receptor structure in, and around, the ion pore. As a final level of control, cytoplasmic determinants control the magnitude (conductance) of ion flow into the cell. Thus the Cys-loop receptors are complex molecular motors, with moving parts, which can transduce extracellular signals across the plasma membrane. Once the full mechanical motions involved are understood, it may be possible to design sophisticated therapeutic agents to modulate their activity, or at least be able to throw a molecular spanner into the works!

Redox modulation of homomeric ρ1 GABAC receptors

“…Similar to other members of the cys-loop receptor superfamily, q 1 GABA C receptor subunits contain two conserved cysteine residues which are separated by 13 amino acids and presumably form a disulphide bridge. This cys-loop is located in the Nterminal domain (Zhang et al 2001;Connolly and Wafford 2004), but is not part of the agonist/antagonist binding pocket Sedelnikova et al 2005). Given the possibility of an external site of action for redox agents and the proposed membrane topology of the GABAq 1 receptor (Zhang et al 2001), these cysteine residues are good candidates to be the redox modulatory sites.…”

“…GABA A and GABA C receptors are GABAgated pentameric chloride (Cl ) ) channels members of the cys-loop-containing neurotransmitter receptor superfamily (Moss and Smart 2001;Connolly and Wafford 2004). Remarkably, GABA C receptors are insensitive to the GABA A competitive antagonist bicuculline (Sivilotti and Nistri 1991) and appear to be exclusively composed of q subunits (q 1 , q 2 , and q 3 ) that yield homomeric and heteromeric receptors (Zhang et al 2001).…”

The role of GABAA receptors in the development of alcoholism

“…Channel opening is initiated by the extracellular association of agonists with discrete binding pockets leading to conformational changes that result in the opening of a central ion pore (Barnard et al, 1998;Connolly and Wafford, 2004;. GABA A receptors have structural and functional homology with a class of cys-loop ligand-gated ion channel receptors including glycine, 5-HT3 and nicotinic acetylcholine.…”

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

“…[7] Both anions and cations can enter the pore where ion filtering is controlled by specific residues lining the narrow region of the pore at the cytoplasmic end of the transmembrane domain (TMD) extending into the TMI-II cytoplasmic loop. [8] A second ion filter controlling ion flow has been observed in the receptor at the intracellular transmembrane TMIII-IV loop. [9] CYS loop receptors share significant structural similarity consisting of a pentameric assembly of subunits with three domains: N-terminal extracellular domain (ECD) with the 15 amino acid CYS-loop disulphide; transmembrane domain with four helices, MI-IV and intracellular domain (ICD) consisting of a long loop between MIII and MIV ( Figure 1).…”