M current

Abstract: K(+) channels play a crucial role in regulating the excitability of neurons. Many K(+) channels are, in turn, regulated by neurotransmitters. One of the first neurotransmitter-regulated channels to be identified, some 25 years ago, was the M channel. This was categorized as such because its activity was inhibited through stimulation of muscarinic acetylcholine receptors. M channels are now known to be composed of subunits of the Kv7 (KCNQ) K(+) channel family. However, until recently, the link between the receptors and the channels has remained elusive. Here, we summarize recent developments that have begun to clarify this link and discuss their implications for physiology and medicine.

Abstract: 1 The actions of serotonin (5-HT) on pyramidal cells of the CA1 region of the rat hippocampus were characterized using intracellular recording in in vitro brain slices 2 5-HT typically evokes a biphasic response consisting of a hyperpolarization which is followed by a longer-lasting depolarization These effects on membrane potential are accompanied by a decrease in the calcium-activated after-hyperpolarization (ahp) 3 Detailed analysis using 5-HT antagonists and agonists indicates that the hyperpolarization is mediated by a 5-HT1A receptor Spiperone is the most effective antagonist of the response and the selective 5-HT1A agonist, 8-OHDPAT, behaves as a partial agonist at this receptor In agreement with the distribution of 5-HT1A binding sites, responses to 5-HT were most prominent in the stratum radiatum 4 The hyperpolarizing response is associated with a decrease in input resistance, is blocked by extracellular barium and intracellular caesium, is unaffected by the chloride gradient, and its reversal potential shifts with the extracellular concentration of potassium as predicted for a response mediated by a selective increase in potassium permeability 5 The depolarizing response and reduction in the ahp could be studied in isolation by blocking the hyperpolarizing response with either pertussis toxin or spiperone The pharmacology of these responses did not correspond to that of any of the 5-HT binding sites reported in CNS tissue Although the depolarization and blockade of the ahp have the same time course it is unclear if they are mediated by the same or different receptors 6 The depolarization most likely results from a decrease in resting potassium conductance However, neither a blockade of the M current nor the ahp current can account for the depolarization 7 Blockade of phosphodiesterase activity by 3-isobutyl-1-methylxanthine (IBMX) did not enhance the depressant action of 5-HT on the ahp, making it unlikely that this action is mediated by cyclic AMP 8 Blockade of the ahp by 5-HT reduces spike frequency adaptation and counteracts the inhibitory action of 5-HT on 5-HT1A receptors This excitatory action outlasts the hyperpolarizing action 9 In summary 5-HT acts on at least two distinct receptors on hippocampal pyramidal cells, one coupled to the opening of potassium channels and a second coupled to a decrease in a resting potassium conductance and a decrease in the ahp

Abstract: 1. Bullfrog lumbar sympathetic neurones were voltage-clamped in vitro through twin micro-electrodes. Four different outward (K(+)) currents could be identified: (i) a large sustained voltage-sensitive delayed rectifier current (I(K)) activated at membrane potentials more positive than -25 mV; (ii) a calcium-dependent sustained outward current (I(C)) activated at similar positive potentials and peaking at +20 to +60 mV; (iii) a transient current (I(A)) activated at membrane potentials more positive than -60 mV after a hyperpolarizing pre-pulse, but which was rapidly and totally inactivated at all potentials within its activation range; and (iv) a new K(+) current, the M-current (I(M)).2. I(M) was detected as a non-inactivating current with a threshold at -60 mV. The underlying conductance G(M) showed a sigmoidal activation curve between -60 and -10 mV, with half-activation at -35 mV and a maximal value (G(M)) of 84+/-14 (S.E.M.) nS per neurone. The voltage sensitivity of G(M) could be expressed in terms of a simple Boltzmann distribution for a single multivalent gating particle.3. I(M) activated and de-activated along an exponential time course with a time constant uniquely dependent upon voltage, maximizing at approximately 150 ms at -35 mV at 22 degrees C.4. Instantaneous current-voltage (I/V) curves were approximately linear in the presence of I(M), suggesting that the M-channels do not show appreciable rectification. However, the time- and voltage-dependent opening of the M-channels induced considerable rectification in the steady-state I/V curves recorded under both voltage-clamp and current-clamp modes between -60 and -25 mV. Both time- and voltage-dependent rectification in the voltage responses to current injection over this range could be predicted from the kinetic properties of I(M).5. It is suggested that I(M) exerts a strong potential-clamping effect on the behaviour of these neurones at membrane potentials subthreshold to excitation.

Abstract: Coherent network oscillations in the brain are correlated with different behavioural states. Intrinsic resonance properties of neurons provide a basis for such oscillations. In the hippocampus, CA1 pyramidal neurons show resonance at theta (theta) frequencies (2-7 Hz). To study the mechanisms underlying theta-resonance, we performed whole-cell recordings from CA1 pyramidal cells (n = 73) in rat hippocampal slices. Oscillating current injections at different frequencies (ZAP protocol), revealed clear resonance with peak impedance at 2-5 Hz at approximately 33 degrees C (increasing to approximately 7 Hz at approximately 38 degrees C). The theta-resonance showed a U-shaped voltage dependence, being strong at subthreshold, depolarized (approximately -60 mV) and hyperpolarized (approximately -80 mV) potentials, but weaker near the resting potential (-72 mV). Voltage clamp experiments revealed three non-inactivating currents operating in the subthreshold voltage range: (1) M-current (I(M)), which activated positive to -65 mV and was blocked by the M/KCNQ channel blocker XE991 (10 microM); (2) h-current (I(h)), which activated negative to -65 mV and was blocked by the h/HCN channel blocker ZD7288 (10 microM); and (3) a persistent Na(+) current (I(NaP)), which activated positive to -65 mV and was blocked by tetrodotoxin (TTX, 1 microM). In current clamp, XE991 or TTX suppressed the resonance at depolarized, but not hyperpolarized membrane potentials, whereas ZD7288 abolished the resonance only at hyperpolarized potentials. We conclude that these cells show two forms of theta-resonance: "M-resonance" generated by the M-current and persistent Na(+) current in depolarized cells, and "H-resonance" generated by the h-current in hyperpolarized cells. Computer simulations supported this interpretation. These results suggest a novel function for M/KCNQ channels in the brain: to facilitate neuronal resonance and network oscillations in cortical neurons, thus providing a basis for an oscillation-based neural code.