J Physiol 587.9 (2009) pp 1859–1860 1859

PERSPECT IVES

O2 sensing in chromaffin cells:new duties for T-type channels

Emilio Carbone and Valentina CarabelliDepartment of Neuroscience, NIS Center,CNISM Research Unit, 10125 Torino, Italy

Email: emilio.carbone@unito.it

T-type Cav3 channels are voltage-gatedCa2+ channels that are able to sustainkey physiological functions such aslow-threshold spikes generation, neuronaland cardiac pacemaking, musclecontraction, hormone release, cell growthand differentiation. This mainly derivesfrom the unique property of T-typechannels that activate at rather negativevoltages (∼ −60 mV). These channelsare ubiquitous in most excitable tissuesand their expression at sufficient densitieslowers the threshold of action potentialgeneration with a consequent increase ofcell excitability. The chromaffin cells ofadult adrenal medulla seemed to escape thisgeneral rule, but recent works have shownthat during chronic hypoxia or underβ-adrenergic stimulation, chromaffin cellsalso acquire sufficiently high densities ofCav3.2 T-type channels, which lower theresting membrane potential and sustainlow-threshold spike activity (Carbone et al.2006; Carabelli et al. 2007). Recruitmentof T-type channels is not a unique featureof chromaffin cells. PC12 cells also expressCav3.2 channels during exposure tochronic hypoxia, the effect being mediatedby hypoxia-inducible factors (HIFs) (DelToro et al. 2003).

An intriguing question is why chromaffincells should recruit new T-type channelsduring chronic hypoxia when they arealready well equipped with high- (N,P/Q) and mid-threshold (L and R) Ca2+

channel types that control chromaffin cellfiring activity and catecholamine secretion.An easy answer is that T-type channelavailability increases cell excitability andbroadens the range of membrane voltageat which adrenaline and noradrenaline aresecreted, assuming that T-type channels arecoupled to exocytosis with the same efficacyas other voltage-gated Ca2+ channels.Indeed, Cav3.2 channels are effectivelycoupled to secretion with the same Ca2+

efficacy of L-, N-, P/Q- and R-type channels(Giancippoli et al. 2006), thus proving thatT-types do not only participate in loweringthe threshold of cell excitability but alsocontribute to exocytosis (and possibly toendocytosis) in adult chromaffin cells. Thisnewly uncovered duty of T-type channelsopens a further critical question. Arethe Cav3.2 channels available only duringpathological states of adrenal chromaffincells (chronic hypoxia, intense β-adrenergicstimulation, etc.) or do they serve some keyphysiological role during adrenal medulladevelopment and maturation?

The paper by Levitsky & Lopez-Barneo(2009) that appears in this issue ofThe Journal of Physiology furnishes afull answer to this question and proves,in a very elegant way, that T-typechannels are indeed functionally expressedin neonatal rat chromaffin cells andhelp in sensing acute-hypoxia conditions.At the early developmental stage, theadrenal medulla acts as an O2 sensor(Seidler & Slotkin, 1985), respondingto acute hypoxia by releasing adequateamounts of catecholamines, which criticallyregulate neonatal survival and adaptation toextra-uterine life. Catecholamines stimulatecardiac activity and prepare the lungs forair breathing. Levitsky & Lopez-Barneoclearly show that neonatal rat chromaffincells respond to acute hypoxia with anincreased rate of catecholamine secretionthat is strongly attenuated by the sameNi2+ concentration that reversibly blocksCav3.2 channels. Since T-type channels inchromaffin cells open by mild membranedepolarization (Carabelli et al. 2007), itis likely that acute hypoxia causes thefast closing of K+ channels and sub-sequent openings of T-type channels.Ca2+ entry through these channels causesthe acute hypoxia-evoked secretion ofcatecholamines.

The paper also shows that when O2

sensing disappears in adult chromaffincells following splanchnic innervation, theexpression of functioning T-type channelsis also switched off, to reappear againwith the O2 sensitivity when the adultadrenal medulla is artificially denervated.Thus, T-type channels and O2 sensingappear critically linked in the absenceof the sympathetic neurogenic control ofchromaffin cell activity. The work highlights

the relevant role that T-type channels playin the control of Ca2+-dependent exocytosisevoked by acute hypoxia in neonatalchromaffin cells and opens new inter-esting issues concerning the mechanismsby which a cell up-regulates the levels oflow-threshold Ca2+ channels during thefetal stage or down-regulates during cellmaturation. An open issue is the rolethat cholinergic innervation plays in theseprocesses, possibly through a Ca2+-drivenmechanism which is probably activatedby an increased Ca2+ entry through opennicotinic receptors (nAChRs). A secondopen issue is the possibility that othervoltage-gated Ca2+ channels may contributeto O2 sensing in neonatal chromaffincells, as this possibility has not been fullyinvestigated in the present work.

The findings by Levitsky and Lopez-Barneo have great physiologicalrelevance and might also have importantpathophysiological implications. Forinstance, T-type channel down-regulationin chromaffin cells might be one of thecauses of sudden infant death syndrome(SIDS), a disorder associated with decreasedchemoreceptor excitability. Clinical studiessuggest that cigarette smoking is one ofthe major risk factors for SIDS. Chronicnicotine in utero suppresses the sensitivityof chromaffin cells to hypoxia by favouringfetal and postnatal death (Buttgieg et al.2008). Through the activation of nAChRs,nicotine in fetal blood might act as awrong stimulus of premature adrenalmedulla innervations with consequentdown-regulation of functioning T-typechannels. In this way, nicotine-evokedsuppression to acute hypoxia may directlyderive from an abnormally low T-typechannel expression in neonatal chromaffincells.

Obviously, the molecular mechanismsby which T-type channels controlcatecholamine secretion and O2 sensingrequire further investigation. They areof great interest in light of the possibleadverse effects that any malfunctioning ofthe sympathoadrenal system might have onthe overall body function.

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C© 2009 The Authors. Journal compilation C© 2009 The Physiological Society DOI: 10.1113/jphysiol.2009.172197

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C© 2009 The Authors. Journal compilation C© 2009 The Physiological Society