Electrophysiology of ionotropic GABA receptors

Abstract

GABA_A receptors are ligand-gated chloride channels and ionotropic receptors of GABA, the main inhibitory neurotransmitter in vertebrates. In this review, we discuss the major and diverse roles GABA_A receptors play in the regulation of neuronal communication and the functioning of the brain. GABA_A receptors have complex electrophysiological properties that enable them to mediate different types of currents such as phasic and tonic inhibitory currents. Their activity is finely regulated by membrane voltage, phosphorylation and several ions. GABA_A receptors are pentameric and are assembled from a diverse set of subunits. They are subdivided into numerous subtypes, which differ widely in expression patterns, distribution and electrical activity. Substantial variations in macroscopic neural behavior can emerge from minor differences in structure and molecular activity between subtypes. Therefore, the diversity of GABA_A receptors widens the neuronal repertoire of responses to external signals and contributes to shaping the electrical activity of neurons and other cell types.

Keywords: GABAA subtypes; Neuronal inhibition; Neurotransmitter; Phasic currents; Synaptic receptor; Tonic activity.

Fig. 1

GABA_A receptor structure and gating. a Structure of an isolated GABA_A receptor subunit and of a mature receptor. Five subunits, potentially belonging to different classes or isoforms, assemble into a channel permeable to chloride and bicarbonate ions. Ions flow through GABA_A receptors down their electrochemical gradient. b Control of GABA_A receptor conductance by the receptor conformation. The central pore can be either closed or open as a result of agonist fixation on the receptor. In this example, the receptor is viewed from the extracellular space and the subunits are ordered as in the most abundant subtypes, namely αβγ. The presence of two GABA binding sites corresponds to ternary receptors (composed of subunits from three different classes)

Fig. 2

General characteristics of GABA_A receptor-mediated currents. a Typical GABA_A receptor current time-course and kinetic electrophysiological parameters. b Dependence of GABA_A receptor-mediated current intensity on agonist concentration for different Hill coefficients

Fig. 3

Markovian models of receptor channel activity. a Simplest Markovian model of a receptor channel, with two unitary states: open (O) and closed (C). The transition rates describing channel opening and closure are respectively k_o and k_c. Both transition rates are a function of the agonist concentration [A]. b Application of the two-states model to steady-state situations. K is the equilibrium constant, and depends on agonist concentration. c MWC model. L, r and K are constants depending on receptor structure and [G] is the GABA concentration. The open states are O (no GABA bound), OG (one GABA) and OG₂ (two GABA); likewise, C, CG and CG2 are the close states

Fig. 4

Characteristics of GABA_A receptor desensitization. a Rundown. When GABA_A receptors are exposed to frequent GABA transients, a portion of the receptor population desensitizes at each transient and does not recover before the next exposure, resulting in a decrease in peak amplitude. b Biphasic desensitization. The current decay upon desensitization can often be modeled as the sum of two decreasing exponential components. A global desensitization rate can be computed from the characteristic time (τ) of each component.

Fig. 5

Relationships between microscopic and macroscopic kinetics of channel opening. Deactivation is a macroscopic property resulting from the integration of single-channel currents time-courses. Its characteristic time (τ) is longer than mean channel open time due to possible channel reopening events and is increased by desensitization due to the possible reactivation of desensitized channels

Fig. 6

Effects of spillover on GABA_A receptor-mediated post-synaptic currents. Phasic activity occurs upon the fixation of GABA by GABA_A receptors on the post-synaptic neuron. Spillovers from nearby synapses can desensitize part of the receptors and decrease the amplitude of the next IPSC

Fig. 7

Comparison of phasic and tonic currents. a Phasic current. 1: due to the high GABA EC50 of most phasic receptors, background GABA transients do not activate GABA_A receptors. 2: fast activation. 3: high amplitude current peak. 4: slow deactivation. 5: rundown. b Tonic current. 1: slow activation. 2: steady-state, low-amplitude current with limited desensitization

Fig. 8

Presynaptic inhibition of action potentials mediated by GABA_A receptors. Inhibitory currents mediated by GABA_A receptors can inhibit simultaneous action potentials, and allow different axonal ramifications to convey different signals

Fig. 9

Ionic modulation of the GABA_A receptor. Ion flows are represented with black arrows, activation with green arrows and inhibition with red arrows. Dashed lines indicate subtype specificity