Review
New insights into the therapeutic potential of Girk channels

https://doi.org/10.1016/j.tins.2013.10.006Get rights and content

Highlights

  • Girk channels are novel targets for therapeutic interventions in a broad array of human nervous system disorders.

  • Girk channels exist in multiprotein complexes whose molecular composition can differ to suit the needs of the cell under specific circumstances.

  • Girk signaling shapes many of the behavioral effects of drugs of abuse, including opioids, cocaine, methamphetamine, and ethanol.

  • Plasticity of Girk signaling triggered by neuronal activity and by drugs of abuse involves subcellular redistribution of the channel.

G protein-dependent signaling pathways control the activity of excitable cells of the nervous system and heart, and are the targets of neurotransmitters, clinically relevant drugs, and drugs of abuse. G protein-gated inwardly rectifying potassium (K+) (Girk/Kir3) channels are a key effector in inhibitory signaling pathways. Girk-dependent signaling contributes to nociception and analgesia, reward-related behavior, mood, cognition, and heart-rate regulation, and has been linked to epilepsy, Down syndrome, addiction, and arrhythmias. We discuss recent advances in our understanding of Girk channel structure, organization in signaling complexes, and plasticity, as well as progress on the development of subunit-selective Girk modulators. These findings offer new hope for the selective manipulation of Girk channels to treat a variety of debilitating afflictions.

Section snippets

Introduction to Girk signaling

Signal transduction involving inhibitory (Gi/o) G proteins titrates the excitability of neurons, cardiac myocytes, and endocrine cells, actions crucial for regulating mood and cognition, nociception and antinociception, reward, energy homeostasis, motor activity and coordination, hormone secretion, and cardiac output. Not surprisingly, dysregulation of Gi/o-dependent signaling has been linked to several neurological and cardiac disorders. Given this, and because the efficacy of many clinically

Girk channel structure

Girk channels are tetramers formed by differential multimerization among the products of four genes: Girk1/Kir3.1/Kcnj3, Girk2/Kir3.2/Kcnj6, Girk3/Kir3.3/Kcnj9, and Girk4/Kir3.4/Kcnj5 1, 2 (Figure 1A). Each Girk subunit possesses intracellular N- and C-terminal domains, and two transmembrane segments that flank a hydrophobic pore domain. Random assembly theoretically allows the formation of many distinct Girk channel subtypes, and alternative splicing of Girk1 and Girk2 gene mRNAs potentially

Macromolecular organization of Girk signaling

Girk channels are thought to exist in multiprotein complexes that include GPCRs, G proteins, and regulatory proteins 1, 2, 31, a consensus that has emerged despite the fact that relatively few protein–protein interactions involving Girk channels have been demonstrated using classical biochemical approaches or native systems. Indeed, most reported interactions have involved overexpression of Girk subunits and putative binding partners in cell types that do not normally express Girk channels.

Plasticity of Girk signaling

Recent work has shown that the strength and sensitivity of neuronal Girk signaling is titratable and subject to regulation by multiple stimuli. The first clear example of Girk signaling plasticity came with the demonstration that stimulation protocols that evoked NMDA receptor-dependent long-term potentiation (LTP) of glutamatergic neurotransmission in hippocampal CA1 neurons also strengthened synaptic GABAB–Girk signaling [70]. Subsequent work in cultured hippocampal pyramidal neurons revealed

Pharmacologic manipulation of Girk channels

Given the broad distributions and roles of Girk channels in the nervous system, and their contributions to cardiac and endocrine physiology, global and direct pharmacologic manipulation of Girk signaling should evoke an array of consequences, many undesirable (Table 1). Indeed, global constitutive ablation of Girk2 triggers an array of phenotypes, most notably a shortened lifespan due to spontaneous lethal seizures [74]. Although constitutive ablation of other Girk subunits correlates with

Concluding remarks

Although several outstanding questions remain (Box 2), efforts by many research groups over the last two decades have revealed key functional, structural, and regulatory features of Girk channels. This body of evidence, combined with our evolving understanding of Girk channel contributions to physiology and disease, and a continually improving capacity for pharmacologic manipulation, set the stage for an exciting future of investigations into the therapeutic potential of this interesting and

Acknowledgments

This work was supported by National Institutes of Health (NIH) grants to K.W. (MH061933, HL105550, and DA034696) and by the Spanish Ministry of Science and Innovation BFU2012-38348 and CONSOLIDER-Ingenio CSD2008-0000 (to R.L.). The authors thank members of the Wickman and Luján laboratories for their suggestions for the manuscript.

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      Citation Excerpt :

      GIRK2 deletion abolishes GPCR-GirK postsynaptic currents, but does not seem to cause changes in the presynaptic inhibition mediated by the same neurotransmitters (Luscher et al., 1997). However, some authors suggest that GirK channels do contribute to presynaptic inhibition (Lujan et al., 2014) as has been observed for neurotransmitter release in some cortical neurons (Davies, Starkey, Pozza, & Collingridge, 1991; Ladera et al., 2008) (see the description about GABAergic control of GirK channels in section 4.1). GirK channels also play a role in neuronal self-inhibition, and it has been described that some cortical neurons mediate their own hyperpolarization by endocannabinoids release, which bind to GPCR acting on GirK channels present in the dendrites of those same neurons (Luscher & Slesinger, 2010).

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