GTP-binding proteins mediate transmitter inhibition of voltage-dependent calcium channels

Abstract

The modulation of voltage-dependent calcium channels by hormones and neurotransmitters has important implications for the control of many Ca²⁺-dependent cellular functions including exocytosis and contractility^1–7. We made use of electrophysiological techniques, including whole-cell patch-clamp recordings from dorsal root ganglion (DRG) neurones, to demonstrate a role for GTP-binding proteins (G-proteins) as signal transducers in the noradrenaline- and γ-aminobutyric acid (GABA)-induced inhibition of voltage-dependent calcium channels^8–11. This action of the transmitters was blocked by: (1) preincubation of the cells with pertussis toxin (a bacterial exotoxin catalysing ADP-ribosylation of G-proteins¹²); or (2) intracellular administration of guanosine 5′-O-(2-thiodiphosphate) (GDP-β-S), a non-hydrolysable analogue of GDP that competitively inhibits the binding of GTP to G-proteins¹³. Our findings provide the first direct demonstration of the G-protein-mediated inhibition of voltage-dependent calcium channels by neurotransmitters. This mode of transmitter action may explain the ability of noradrenaline and GABA to presynaptically inhibit Ca²⁺-dependent neurosecretion from DRG sensory neurones^4,5.