Novel coupling is painless

The first report that several neurotransmitters, including -aminobutyric acid (GABA), decreased neuronal action potential duration in dorsal root ganglia (DRG) neurons appeared more than 35 years ago (Dunlap and Fischbach, 1978). Dunlap and Fischbach (1978) realized that the effects of GABA could not occur via the ionotropic GABA receptor—at that time the only known GABA receptor—and that the target ion channel was most likely a voltage-gated calcium (Ca V) channel, rather than a Na V or K V channel. They correctly concluded that another type of GABA receptor must exist, which we now know is the G protein–coupled GABA type B (GABA B) receptor. The modulated channel was later identified as the chick homologue of the N-type Ca 2+ channel Ca V 2.2 ( 1 B) (Cox and Dunlap, 1992), one of three members of the Ca V 2 family. GABA B receptors in human and rodent sensory neurons and in various expression systems were shown subsequently to inhibit native N-current and recombinant Ca V 2.2 current, respectively (Raingo et al., 2007; Callaghan et al., 2008; Adams and Berecki, 2013). Inhibition primarily occurs by a voltage-dependent mechanism common to various neurotransmitters whereby G binds to Ca V 2.2 slowing channel opening, whereas positive voltage steps relieve this inhibition (Marchetti et al., 1986). The closely related P/Q-type ( 1 A) channel, Ca V 2.1, exhibits similar modulation by GABA (Mintz and Bean, 1993). The third member of the Ca V 2 family, Ca V 2.3 ( 1 E), is less susceptible to direct G modulation than the other two family members (Shekter et al., 1997). The revelation that mice with a deletion in either Ca V 2.2 or in Ca V 2.3 exhibited reduced neuropathic pain–like behavior, indicating that these channels participate in pain sensation signaling (Saegusa et al., 2000, 2001), sparked great interest in the regulation of Ca V 2 inhibition by GABA B receptors in DRG neurons. Astonishingly, however, the precise mechanism of GABA B receptor modulation of Ca V 2.3 channels has remained ill defined. Given Ca V 2.3's functional importance in pain pathways , the uncertainty surrounding whether GABA B receptors modulate Ca V 2.3 seems remarkable. Several observations may provide insights as to why this question still awaits an answer. In neurons, native Ca V 2.3 is referred to as R-type current, which is poorly defined as the current remaining after blocking the activity of T …