Calcium Channels Transmitter Release

When an action potential arrives at the axon terminal, it induces the release of a chemical transmitter. Transmitter release is a Ca2+-dependent process (see Chapter 4) and requires a charge of Ca2+. This is provided through the action potential-induced

Table 2.1 Types of calcium channel

Type

T

L

N

P/Q

R

a-subunit(s)

1G,H,I

1C,D

IB

1A

1E

Threshold1

Low

High

High

High

High

Inactivation

Fast

Slow

Moderate

None (P)

Fast

Moderate (Q)

Location2

s/d

s/d

t,s/d

t,s/d

t,s/d

Blockers

Ni2+

DHP3

w-CTX-GVIA4

w-Aga IVA5

Main functions

Pacemaker

Spike

Transmitter

Transmitter

Transmitter

release

release

release

!Low threshold around — 60 mV; high threshold around — 40 mV.

3Dihydropyridines.

4ffl-Conotoxin GVIA.

5ffl-Agatoxin IVA.

!Low threshold around — 60 mV; high threshold around — 40 mV.

3Dihydropyridines.

4ffl-Conotoxin GVIA.

5ffl-Agatoxin IVA.

opening of voltage-gated Ca2+ channels. A variety of Ca2+ channels have been described, characterised by their kinetics, single-channel properties, pharmacology (especially sensitivity to different toxins) and molecular structure (Table 2.1). Those primarily responsible for transmitter release belong to the N (a1B), P/Q (a1A) and R classes (a1E). So far, no pharmacological agents capable of uniquely modifying Ca2+ channels involved in transmitter release have been described (other than polypeptide toxins). These, and other (L-type, T-type), Ca2+ channels are also variably present in neurons somata and/or dendrites, where they contribute to the regulation of neural activity in other ways (see below).

REGULATION OF Ca2+ CHANNELS BY NEUROTRANSMITTERS

N and P/Q channels are susceptible to inhibition by many neurotransmitters and extracellular mediators that act on receptors coupling to Pertussis toxin-sensitive G-proteins (primarily Go) — for example, noradrenaline (via a2 receptors), acetylcholine (via M2 and M4 muscarinic receptors), GABA (via GABA-B receptors), opioid peptides (via receptors) and adenosine (via A2 receptors) (see Fig. 2.4). Inhibition results from the release of the fiy subunits of the trimeric (a^Sy) G-protein following its activation by the receptor. The fiy subunit then binds to the Ca2+ channel in such a way as to shift its voltage sensitivity to more positive potentials, so that the channels do not open as readily during a rapid membrane depolarisation. This effect is 'reversible' in the sense that it can be temporarily reversed by applying a brief, strong depolarisation but then returns on rehyperpolarisation in the continued presence of free fiy subunits (Fig. 2.4(a)). One interpretation of this is that the binding of the fiy subunits is itself voltage-dependent. It should be noted that no 'second messenger' is necessary for this form of inhibition: instead, the fiy subunit reaches, and binds to, a neighbouring Ca2+ channel when released from the activated Go protein. (This G-protein is very abundant in nerve cell membranes.) As a result, the process of inhibition can be quite fast — within 3050 ms following receptor activation. This is thought to provide the principal mechanism responsible for presynaptic inhibition, whereby neurotransmitters inhibit their own release (autoinhibition) during high-frequency synaptic transmission. This process can be replicated by applying exogenous transmitters or their analogues (see Fig. 2.4(b))

Figure 2.3 Role of K+ channels in action potential repolarisation in mammalian axons, revealed using the K+ channel blocking agent, 4-aminopyridine (4-AP, 0.5 mM). Records show intra-axonal recordings from (a) a regenerating sciatic nerve axon following nerve crush; (b) a normal sciatic nerve axon; and (c) a demyelinated ventral root axon after treatment with lysopho-sphatidylcholine. Note that 4-AP prolongs the action potential in (a) and (c) but not in (b). Thus, current through 4-AP-sensitive K+ channels contributes to action potential repolarisation in premyelinated or demyelinated mammalian axons, whereas in normal myelinated axons repolarisation is entirely due to Na+ channel inactivation. (Adapted from Fig. 2 in Trends Neurosci 13: Black, JA et al. Ion Channel Organization of the Myelinated Fiber, p 48-54 (1990) with permission from Elsevier Science

Figure 2.3 Role of K+ channels in action potential repolarisation in mammalian axons, revealed using the K+ channel blocking agent, 4-aminopyridine (4-AP, 0.5 mM). Records show intra-axonal recordings from (a) a regenerating sciatic nerve axon following nerve crush; (b) a normal sciatic nerve axon; and (c) a demyelinated ventral root axon after treatment with lysopho-sphatidylcholine. Note that 4-AP prolongs the action potential in (a) and (c) but not in (b). Thus, current through 4-AP-sensitive K+ channels contributes to action potential repolarisation in premyelinated or demyelinated mammalian axons, whereas in normal myelinated axons repolarisation is entirely due to Na+ channel inactivation. (Adapted from Fig. 2 in Trends Neurosci 13: Black, JA et al. Ion Channel Organization of the Myelinated Fiber, p 48-54 (1990) with permission from Elsevier Science

Untreated PTX-treated

Figure 2.4 Noradrenergic inhibition of Ca2+ currents and transmitter release in sympathetic neurons and their processes, (a) Inhibition of currents through N-type Ca2+ channels by external application of noradrenaline (NA) or by over-expression of G-protein p1 subunits, recorded from the soma and dendrite of a dissociated rat superior cervical sympathetic neuron, Currents were evoked by two successive 10 ms steps from — 70 mV to OmV, separated by a prepulse to +90 mV, Note that the transient inhibition produced by NA (mediated by the G-protein Go) and the tonic inhibition produced by the G-protein p1 y2 subunits were temporarily reversed by the +90 mV depolarisation, (Adapted from Fig, 4 in Delmas, P et al, (2000) Nat. Neurosci. 3: 670678. Reproduced with permission), (b) Inhibition of noradrenaline release from neurites of rat superior cervical sympathetic neurons by the a2-adrenoceptor stimulant UK-14,304, recorded amperometrically, Note that pretreatment with Pertussis toxin (PTX), which prevents coupling of the adrenoceptor to Go, abolished inhibition, (Adapted from Fig, 3 in Koh, D-S and Hille, B (1997) Proc. Natl. Acad. Sci. USA 1506-1511, Reproduced with permission)

Figure 2.4 Noradrenergic inhibition of Ca2+ currents and transmitter release in sympathetic neurons and their processes, (a) Inhibition of currents through N-type Ca2+ channels by external application of noradrenaline (NA) or by over-expression of G-protein p1 subunits, recorded from the soma and dendrite of a dissociated rat superior cervical sympathetic neuron, Currents were evoked by two successive 10 ms steps from — 70 mV to OmV, separated by a prepulse to +90 mV, Note that the transient inhibition produced by NA (mediated by the G-protein Go) and the tonic inhibition produced by the G-protein p1 y2 subunits were temporarily reversed by the +90 mV depolarisation, (Adapted from Fig, 4 in Delmas, P et al, (2000) Nat. Neurosci. 3: 670678. Reproduced with permission), (b) Inhibition of noradrenaline release from neurites of rat superior cervical sympathetic neurons by the a2-adrenoceptor stimulant UK-14,304, recorded amperometrically, Note that pretreatment with Pertussis toxin (PTX), which prevents coupling of the adrenoceptor to Go, abolished inhibition, (Adapted from Fig, 3 in Koh, D-S and Hille, B (1997) Proc. Natl. Acad. Sci. USA 1506-1511, Reproduced with permission)

and suppressed by blocking the presynaptic receptors with antagonist drugs, which thereby selectively enhance the release of individual transmitters.

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    When an action potential arrives at the axon terminal it induces?
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