Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several neurotransmitters act through G-protein-coupled receptors to evoke a 'slow' excitation of neurons. These include peptides, such as substance P and neurotensin, as well as acetylcholine and noradrenaline. Unlike the fast (approximately millisecond) ionotropic actions of small-molecule neurotransmitters, the slow excitation is not well understood at the molecular level, but can be mainly attributed to suppressing K(+) currents and/or activating a non-selective cation channel. The molecular identity of this cation channel has yet to be determined; similarly, how the channel is activated and its relative contribution to neuronal excitability induced by the neuropeptides are unknown. Here we show that, in the mouse hippocampal and ventral tegmental area neurons, substance P and neurotensin activate a channel complex containing NALCN and a large previously unknown protein UNC-80. The activation by substance P through TACR1 (a G-protein-coupled receptor for substance P) occurs by means of a unique mechanism: it does not require G-protein activation but is dependent on Src family kinases. These findings identify NALCN as the cation channel activated by substance P receptor, and suggest that UNC-80 and Src family kinases, rather than a G protein, are involved in the coupling from receptor to channel.
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PMID:Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80. 1909 7

Ion channels can be regulated by a wide spectrum of neurotransmitters and hormones, largely through G-protein-coupled receptors (GPCRs). G-protein-independent activation of ion channel currents by GPCRs has also been recorded, although the molecular identity of the channels and the activation mechanisms remain largely unknown. UNC80 is a protein that is associated with the NALCN Na(+) leak cation channel, and is required for the activation of this channel by the neuropeptide substance P through GPCRs in a G-protein-independent fashion. Here, we show that UNC80 binds Src kinases and recruits Src into the channel complex. This finding is consistent with the known requirement for Src kinases in the activation of NALCN, and may lead to new insights into the molecular mechanisms underlying G-protein-independent activation of the channel.
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PMID:UNC80 functions as a scaffold for Src kinases in NALCN channel function. 1953 18

Interstitial cells of Cajal (ICCs) are the pacemaking cells in the gastrointestinal muscles that generate the rhythmic oscillations in membrane potential known as slow waves. ICCs also mediate or transduce inputs from the enteric nervous system. Substance P (SubP) is a member of the family of mammalian tachykinin peptides that are predominantly released by enteric neurons. This study assessed the relationship of Na(+)-leak channel (NALCN) in the SubP-induced depolarization in pacemaking activity in the gastrointestinal tract. The patch-clamp technique for whole-cell recording was used in cultured cluster and single ICCs. Electrophysiological and pharmacological properties of SubP in ICC pacemaking activity were similar to those of NALCN. Reverse-transcription polymerase chain reaction, Western blotting, and immunohistochemistry all showed abundant and localized expression of NALCN messenger RNA and protein in mouse small intestine. NALCN is involved in the SubP-induced depolarization of intestinal pacemaking activity. The protein is a potential target for pharmacological treatment of motor disorders of the gut.
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PMID:Involvement of Na(+)-leak channel in substance P-induced depolarization of pacemaking activity in interstitial cells of Cajal. 2250 57

Spinal projection neurons convey nociceptive signals to multiple brain regions including the parabrachial (PB) nucleus, which contributes to the emotional valence of pain perception. Despite the clear importance of projection neurons to pain processing, our understanding of the factors that shape their intrinsic membrane excitability remains limited. Here, we investigate a potential role for the Na leak channel NALCN in regulating the activity of spino-PB neurons in the developing rodent. Pharmacological reduction of NALCN current (INALCN), or the genetic deletion of NALCN channels, significantly reduced the intrinsic excitability of lamina I spino-PB neurons. In addition, substance P (SP) activated INALCN in ascending projection neurons through downstream Src kinase signaling, and the knockout of NALCN prevented SP-evoked action potential discharge in this neuronal population. These results identify, for the first time, NALCN as a strong regulator of neuronal activity within central pain circuits and also elucidate an additional ionic mechanism by which SP can modulate spinal nociceptive processing. Collectively, these findings indicate that the level of NALCN conductance within spino-PB neurons tightly governs ascending nociceptive transmission to the brain and thereby potentially influences pain perception.
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PMID:NALCN channels enhance the intrinsic excitability of spinal projection neurons. 2974 49