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)

The large B cells of bull-frog sympathetic ganglia are well known to be depolarized by slow synaptic transmission, muscarinic agonists, analogues of luteinizing hormone-releasing hormone (LHRH), and substance P. Voltage-clamp analysis shows that these actions result from two underlying mechanisms: inhibition of the M-current, a voltage-dependent potassium current; and in some cells, an inward current associated with an increase in conductance. The additional inward current appears as a voltage-insensitive change in the instantaneous conductance (i.e. apparent leak conductance). The additional inward current is typically slower in onset and offset than is M-current inhibition. It is typically seen for higher concentrations and longer durations of agonist application. In many cells, only a decrease in M-current can be demonstrated. Muscarine inhibits the M-current with 50% inhibition (I50) at 0.7 microM. At least 86% of the M-current is muscarine sensitive. At comparable concentrations, oxotremorine produces less M-current inhibition than does muscarine. Some analogues of teleost LHRH (T-LHRH) are more potent as M-current inhibitors than T-LHRH itself. Those peptides tend to act more slowly than T-LHRH. Substance P shows variable potency for M-current inhibition, with I50 s ranging from 2 nM to greater than 2 microM on different cells. The response to long applications of substance P desensitizes in some cells, which has not been observed for comparable applications of muscarinic or LHRH agonists. Other tachykinins (including substance K) inhibit the M-current. C-terminal fragments of substance P are ineffective, and M-current inhibition by substance P is not blocked by [D-Pro2,D-Trp7,9]- or [D-Arg1,D-Pro2, D-Trp7,9,Leu11] substance P. The slow muscarinic excitatory post-synaptic potential (e.p.s.p.) produces a graded inhibition of up to 90% of the M-current. Occasional cells show an additional inward current with an associated increase in conductance during the slow e.p.s.p. This effect is less marked than with exogenous muscarinic agonists. The late, slow e.p.s.p., which is produced by stimulation of high threshold C-fibre inputs and is resistant to cholinergic antagonists, also involves M-current inhibition. An additional inward current can be observed in some cells. M-current inhibition (by agonists or slow synaptic potentials) increases the number of spikes produced by a given depolarizing current, often allowing maintained firing. This action is not mimicked by equivalent depolarization, and is still seen when the cell is manually clamped to the original resting potential.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Muscarinic and peptidergic excitation of bull-frog sympathetic neurones. 241 36

Responses to substance P (SP) and to hypogastric nerve stimulation were recorded from voltage-clamped guinea pig inferior mesenteric ganglion (IMG) neurons, and compared with those to muscarine. Muscarine produced a voltage-dependent inward current accompanied by a reduced input conductance and inhibition of IM a time- and voltage-dependent K+-current (Brown and Adams: Nature 283:673-676, 1980). SP also produced an inward current, accompanied by a fall in input conductance (20 out of 31 cells) or a rise in input conductance (7 out of 31 cells). The fall in input conductance was not accompanied by an inhibition of M-current (unlike frog ganglia: Adams et al.: British Journal of Pharmacology 79:330-333, 1983) or an inhibition of the inward rectifier current (unlike globus pallidus neurons: Stanfield et al.: Nature 315:498-501, 1985). Repetitive hypogastric nerve stimulation (10-20 Hz, 2-10 s) produced a slow inward postsynaptic current lasting 1-3 min, with decreases or increases of input conductance matching those produced by SP. The postsynaptic current did not show a consistent or reproducible change in amplitude on varying the holding potential between -90 and -25 mV. It is concluded that SP and hypogastric stimulation produce complex and variable changes in ionic conductance in IMG neurons.
 ...
PMID:Substance P-mediated membrane currents in voltage-clamped guinea pig inferior mesenteric ganglion cells. 246 Sep 61

1. Intracellular microelectrode and whole-cell patch-clamp recordings were obtained from adult guinea pig celiac ganglion neurons grown in tissue culture for 7-14 days. Over 90% of neurons showed phasic-type action-potential discharge with the use of either type of recording electrode; they stained immunohistochemically for catecholamines, tyrosine hydroxylase, and neuropeptide Y. Input resistance (140 M omega) and action-potential amplitude (103 mV) were significantly greater with whole-cell than with microelectrode recordings, but other passive electrical properties were similar. 2. Five potassium currents were characterized: an apamin-sensitive after hyperpolarizing current (IAHP), an apamin and tetraethylammonium-insensitive slow IAHP, an M-like current, a transient outward IA current, and a delayed rectifier IK current. A hyperpolarization-activated cationic Ih current was also present. The first three currents were not observed with whole-cell recordings. 3. Cadmium (200 microM), cobalt (1 mM), lanthanum (30 microM), or a low calcium/high magnesium solution blocked both IAHPS and the M-like current; barium (1 mM) also blocked these currents. 4. Kinetics of the M-like current were best described by a double exponential fit to deactivating tail currents with time constants of 50 and 390 ms at -50 mV. The apamin-sensitive and slow IAHP decayed exponentially with time constants of 145 ms and 3.5 s, respectively. There was no correlation between occurrence of M-like current (95% of neurons) and slow IAHP (40% of neurons), nor any correlation between magnitude of M-like current and IAHP in those cells exhibiting both currents. 5. Muscarine and substance P (SP) caused depolarizations or inward currents (under voltage clamp) at the resting potential (-55 mV) associated with a decreased membrane conductance. The slow IAHP and the M-like current, but not the apamin-sensitive IAHP nor the IA, were blocked by muscarine and SP (IC50 3 microM and 100 nM, respectively). Muscarine and SP also decreased a "leak" potassium current. 6. We conclude that celiac neurons express two calcium-dependent IAHP currents and a calcium-dependent M-current; these are seen by fine-tipped intracellular microelectrodes but not by whole-cell patch electrodes. These currents are not required for spike frequency accommodation. Muscarine and SP reduce these currents, as well as voltage-independent leakage potassium current.
 ...
PMID:Potassium currents and their modulation by muscarine and substance P in neuronal cultures from adult guinea pig celiac ganglia. 768 76

1. The Ca2+ channel subtypes controlling ACh release from basal forebrain neurones and the ionic basis underlying muscarinic receptor-mediated autoinhibition were studied using skeletal myoballs to detect ACh release from individual rat basal forebrain neurones in culture. 2. Somatic Ca2+ currents evoked using a simulated action potential waveform revealed that Ca2+ entry was primarily through N-, Q- and to a lesser extent R-, T- and L-type Ca2+ channels. 3. Muscarine (10 microM) inhibited N- and Q- but not R-, T- or L-type somatic Ca2+ channels. Agonist inhibition was totally blocked by pre-treatment with pertussis toxin (500 ng ml-1). 4. ACh release from discrete sites along basal forebrain neurites (1. 2 mM extracellular Ca2+) could be largely abolished by blocking Ca2+ entry through either N-type or Q-type Ca2+ channels. Inhibition of Ca2+ entry through L- or T-type channels had no effect upon release. Following inhibition of either N- or Q-type Ca2+ channels, release could be restored to near control levels by raising [Ca2+]o. After selectively blocking N-, Q-, L- and T-type channels, low levels of release could still be evoked as a result of Ca2+ entry through R-type Ca2+ channels. 5. Muscarinic receptor activation reversibly inhibited ACh release due to Ca2+ entry through N-, Q- and R-type Ca2+ channels. In contrast, inhibition of inwardly rectifying K+ channels using Ba2+ (3-10 microM) or substance P (0.03-0.1 microM), or block of SK or BK Ca2+-activated K+ channels with apamin (100 nM) or charbydotoxin (100 nM) respectively, had no effect upon either ACh release or its modulation by muscarinic agonists. 6. These results show that ACh release from individual release sites on basal forebrain neurones is controlled by multiple Ca2+ channel subtypes with overlapping Ca2+ microdomains and that autoinhibition of release results from M2 muscarinic receptor-mediated inhibition of these presynaptic Ca2+ channels rather than as a consequence of K+ channel activation.
 ...
PMID:The role of N-, Q- and R-type Ca2+ channels in feedback inhibition of ACh release from rat basal forebrain neurones. 992 81

The involvement of G proteins in the transduction mechanism of M current (Im) inhibition by extracellular ligands in bullfrog sympathetic neurons was examined using the hydrolysis resistant nucleotide analogues GTPgammaS and GDPbetaS. Im was recorded in large (40 - 60 microm) isolated neurons using the patch-clamp technique in the whole-cell configuration, as well as in neurons from the intact ganglion impaled with conventional microelectrodes. In whole-cell recordings Im could be recorded without significant loss for 1 h or more provided ATP was present in the patch pipette. Muscarine, D-Ala6-LHRH, substance P and UTP reversibly inhibited Im in isolated control neurons, with full and rapid recovery of the current following agonist washout. Dialysis of isolated neurons with various concentrations of GTPgammaS (1 - 100 microM) affected, in a dose-dependent manner, the recovery of Im after its inhibition by brief agonist application. With 50 microM GTPgammaS, Im inhibition became completely irreversible. Similarly, the reversibility of Im inhibition by muscarine was reduced or abolished by the iontophoretic injection of GTPgammaS through a second microelectrode into neurons of the intact ganglion. GTPgammaS by itself caused a slow, agonist-independent suppression of Im in dialysed neurons, thus mimicking agonist action. Dialysis of isolated neurons with GDPbetaS (100 - 500 microM) attenuated by half or more the magnitude of Im inhibition by agonist as compared to control neurons. In addition, GDPbetaS attenuated the response of a given neuron to muscarine and D-Ala6-LHRH, and caused slow increase of Im, as a function of dialysis time. Incubation (2 - 72 h, 4 - 36 degrees C) of isolated neurons or intact ganglions with activated pertussis toxin had no effect on the response to muscarine. Toxin injections to experimental animals were equally ineffective. In contrast to Im, the additional inward current with increase in conductance induced by muscarine and D-Ala6-LHRH reversed with agonist washout in GTPgammaS-dialysed neurons, although more slowly than in control neurons. The results in this study indicate that a G protein, possibly pertussis toxin-insensitive, provides a common coupling step linking muscarinic, substance P, D-Ala6-LHRH and UTP receptors to the inhibition of M current.
 ...
PMID:A G Protein Mediates the Inhibition of the Voltage-Dependent Potassium M Current by Muscarine, LHRH, Substance P and UTP in Bullfrog Sympathetic Neurons. 1210 39

The guinea pig bladder is innervated by at least five distinct major classes of extrinsic sensory neurons. In this study, we have examined the mechanisms of mechanotransduction and chemosensitivity of two classes of bladder afferents that have their endings in the vicinity of the urothelium: stretch-sensitive muscle-mucosal mechanoreceptors and stretch-insensitive, mucosal high-responding afferents. The non-selective P2 purinoreceptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid did not affect stretch- or stroking-induced firing of these afferents but significantly reduced the excitatory action of alpha,beta-methylene ATP. Blocking synaptic transmission in Ca(2+)-free solution did not affect stretch-evoked firing but slightly reduced stretch-induced tension responses. Stroking-induced firing of both classes of afferents was also not affected in Ca(2+)-free solution. Of blockers of mechano-gated channels, benzamil (100 microM), but not amiloride (100 microM), Gd(3+) (100 microM) or SKF 96365 (50 microM), inhibited stretch- and stroking-induced firing. Serotonin (100 microM) applied directly onto receptive fields predominantly activated muscle-mucosal afferents. Muscarine (100 microM) and substance P (100 microM) in 24% and 36% cases activated only mucosal high-responding units. Bradykinin (10 microM), but not prostaglandin E2 (10 microM), excites predominantly mucosal units. High (80 mM) K(+) solution activated both afferent classes, but responses of mucosal units were 4 times greater. In contrast to muscle-mucosal units, most mucosal high-responding units were activated by hot Krebs solution (45-46 degrees C), low pH (pH 4) and capsaicin (3 microm). TRPV1 antagonist, capsazepine (10 microM) was without effect on mechanotransduction by mucosal high-responding afferents. The results show that mechanotransduction of these two types of afferents are not dependant upon Ca(2+)-dependent exocytotic release of mediators, or ATP, and it is likely that benzamil-sensitive stretch-activated ion channels on their endings are involved in direct mechanotransduction. The chemosensitivity to agonists and noxious stimuli differs significantly between these two major classes of bladder afferents that reflects their different physiological and pathophysiological roles in the bladder.
 ...
PMID:Mechanotransduction and chemosensitivity of two major classes of bladder afferents with endings in the vicinity to the urothelium. 1960 32