Substance P inhibits activation of calcium‐dependent potassium conductances in guinea‐pig myenteric neurones.

Abstract

SUMMARY1. Intracellular recordings were made from myenteric AH neurones of the guineapig ileum in vitro. Some experiments were done with a single-electrode voltage clamp to measure membrane currents.2. Substance P (SP) applied by superfusion (10 nM-300 nM), pressure ejection (100 nM-10 ftM, 760 mmHg, for 10-20 ms) or ionophoresis (1 mm, 100 nA, for 0-2 s) caused a membrane depolarization and an inward current, associated with a decrease in potassium conductance.3. The SP-induced depolarization was abolished within 15 min by superfusion with calcium-free/high-magnesium (10 mM) solution or solutions containing cobalt, manganese or nickel at 1-3 mm. The response persisted even after 40-60 min of superfusion with calcium-free/normal-magnesium (1-2 mM) solution. In all these solutions, synaptic potentials were abolished within 5 min.4. SP inhibited a slowly developing outward current and an outward tail current during and after a long depolarizing command pulse (2-10 s), and an outward aftercurrent following single or multiple brief depolarizing command pulses (10-50 ms). These outward currents were suppressed in calcium-free/high-magnesium solution.5. SP depressed both a calcium-dependent slow after-hyperpolarization following the action potential and an outward after-current preceded by a brief depolarizing command. Both the SP-induced depolarization and the SP-induced inward current were augmented when the peptide was pressure-ejected during the recovery phase of the slow after-hyperpolarization and during that of the slow outward after-current, but both of them were inhibited or almost abolished when SP was applied immediately after spike initiation or a brief depolarizing command.6. The SP-induced response was depressed by barium (1-2 mM). The SP response was not inhibited by tetraethylammonium at low concentrations (5-10 mm), but was depressed at high concentration (20 mM).7. Superfusion (1-10 nM) or pressure application of a calcium ionophore, A23187, inhibited or even reversed the SP depolarization and the SP-induced inward current.8. These results indicate that SP inhibits activation of a calcium-dependent potassium conductance which contributes to both the slow after-hyperpolarization MS 8113

Characterisation of substance P-induced endocytosis of NK1 receptors on enteric neurons

“…These experiments suggest that receptors on excitatory motor neurons supplying the longitudinal muscle are of the NK3 type and, in the absence of evidence for NK1 or NK2 receptor on the neurons, have led to the general conclusion that neuronal receptors are NK3; conversely, the lack of effect of tetrodotoxin and the effectiveness of NK1 antagonists in reducing contractions elicited by SP have suggested that NK1 receptors are primarily on the muscle (Maggi et al 1990(Maggi et al , 1993. Nevertheless, the potency with which SP depolarises enteric neurons suggests that NK1 receptors are indeed on some neurons; nerve cells are depolarised and excited by SP with threshold concentrations as low as 10 − 10 M and powerful effects are observed with 10 −8 M (Katayama et al 1979;Morita and Katayama 1992). Direct effects on the muscle, deduced to be via NK1 receptors, are also observed at concentrations between 10 −10 M and 10 −8 M (Franco et al 1979;Costa et al 1985;Guard et al 1988).…”

Common ionic mechanisms of excitation by substance P and other transmitters in guinea‐pig submucosal neurones.

“…A voltage-independent background potassium conductance and a voltage-dependent calcium-activated potassium conductance have been shown to be targeted by the so-called slow excitatory transmitters (Katayama & North, 1978;Grafe et al 1980;Surprenant, 1984;Mihara et al 1986; Surprenant, North & Katayama, 1987;Akasu & Tokimasa, 1989;Morita & Katayama, 1992). There is good indirect evidence to suggest that activation of the 'cyclic AMP cascade' is the primary intracellular transduction process involved in closure of potassium channels by most of these substances (Nemeth, Palmer, Wood & Zafirov, 1986;, 1987Akasu & Tokimasa, 1989).…”

Tachykinins as mediators of slow EPSPs in guinea‐pig gall‐bladder ganglia: involvement of neurokinin‐3 receptors.

“…Possibly the most common mechanism leading to substance P-induced depolarizations is a decrease in one or more K+ conductances (Otsuka & Yoshioka, 1993). In the guinea-pig intestine and caecum, substance P depolarizes neurones by suppressing an ongoing Ca2P-activated K+ conductance (Akasu & Tokimasa, 1989;Morita & Katayama, 1992).…”