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The Journal of Neuroscience, May 26, 2004, 24(21):5044-5053; doi:10.1523/JNEUROSCI.0990-04.2004

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Cellular/Molecular
Modulation of Ion Channels and Synaptic Transmission by a Human Sensory Neuron-Specific G-Protein-Coupled Receptor, SNSR4/mrgX1, Heterologously Expressed in Cultured Rat Neurons

Huanmian Chen and Stephen R. Ikeda

Laboratory of Molecular Physiology, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892

Human sensory neuron-specific G-protein-coupled receptors (SNSRs) are expressed solely in small diameter primary sensory neurons. This restricted expression pattern is of considerable therapeutic interest because small nociceptors transmit chronic pain messages. The neuronal function of human SNSRs is difficult to assess because rodent orthologs have yet to be clearly defined, and individual isoforms are found only in a small subset of primary sensory neurons. To circumvent this problem, we expressed human SNSR4 (hSNSR4; also known as Hs.mrgX1) in rat superior cervical ganglion (SCG), dorsal root ganglion (DRG), and hippocampal neurons using nuclear injection or recombinant adenoviruses and examined modulation of ion channels and neurotransmission using whole-cell patch-clamp techniques. BAM8-22 (a 15 amino acid C-terminal fragment of bovine adrenal medulla peptide 22), a peptide agonist derived from proenkephalin, inhibited high (but not low) voltage-activated Ca²⁺ current in both DRG and SCG neurons expressing hSNSR4, whereas no response was detected in control neurons. The Ca²⁺ current inhibition was concentration dependent and partially sensitive to Pertussis toxin (PTX) treatment. Additionally, the peptide was highly effective in modulating current arising from M-type K⁺ channels in SCG neurons expressing hSNSR4. In hippocampal neurons expressing hSNSR4, BAM8-22 induced presynaptic inhibition of transmission that was abolished after PTX treatment. Our data indicate that hSNSR4, when heterologously expressed in rat neurons, can be activated by an opioid-related peptide, couples to G_q/11-proteins as well as PTX-sensitive G_i/o-proteins, and modulates neuronal Ca²⁺ channels, K⁺ channels, and synaptic transmission.

Key words: channel; sympathetic; dorsal root ganglion; nociception; pain; neuropeptide

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Received March 17, 2004; revised April 21, 2004; accepted April 22, 2004.

This article has been cited by other articles:

				H. Chen, H. L. Puhl III, S.-L. Niu, D. C. Mitchell, and S. R. Ikeda Expression of Rem2, an RGK Family Small GTPase, Reduces N-Type Calcium Current without Affecting Channel Surface Density J. Neurosci., October 19, 2005; 25(42): 9762 - 9772. [Abstract] [Full Text] [PDF]

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