This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Boyett, M.R. Articles by Dobrzynski, H. Search for Related Content PubMed PubMed Citation Articles by Boyett, M.R. Articles by Dobrzynski, H.

(Circulation Research. 2007;100:1543.)
© 2007 American Heart Association, Inc.

Editorials

The Sinoatrial Node Is Still Setting the Pace 100 Years After its Discovery

M.R. Boyett, H. Dobrzynski

From the Cardiovascular Research Group, School of Medicine, University of Manchester, Core Technology Facility, Manchester, UK.

Correspondence to Professor M.R. Boyett, Cardiovascular Research Group, School of Medicine, University of Manchester, Core Technology Facility, 46 Grafton Street, Manchester, M13 9NT, UK. E-mail mark.boyett{at}manchester.ac.uk

See related article, pages 1605–1614

Key Words: sinoatrial node • store-operated Ca²⁺ channels • TRP channels • intracellular Ca²⁺ • pacemaking

The mammalian sinoatrial node, the pacemaker of the heart, was discovered 100 years ago in the countryside of Kent (UK) in "a cosy, squat, red-roofed farm-house, embowered in creepers, separated from the road by a richly stocked garden" with "a horse going round and round winding up a huge bucket from a very deep well" and a "farmyard, filled with healthy farmyard manure".¹ Arthur Keith (later Sir Arthur) had converted the drawing room into a laboratory and recruited the assistance of Martin Flack, the son of the local butcher and grocer and a young medical student at the time.¹ One evening when Keith and his wife, Celia, returned from a bicycle ride, Flack showed him a "wonderful structure" he had discovered in the heart of a mole (perhaps caught on the farm?)—so was discovered the sinoatrial node. Keith and Flack published the discovery of the sinoatrial node in 1907 in the Journal of Anatomy and Physiology.² Curiously, only a few years later, Keith was to become embroiled in one of the biggest scientific scandals of all time, ‘Piltdown man’, a fraudulent ‘missing link’. Now 100 years after the discovery of the sinoatrial node, we are still making new discoveries about the workings of the sinoatrial node as shown by the paper from Ju and Allen and colleagues in this issue of Circulation Research—the sinoatrial node is still setting the pace!³

In the 1970s and 1980s a flurry of voltage clamp studies, first on multicellular preparations of sinoatrial node tissue and then on isolated sinoatrial node cells, appeared to establish the mechanism of pacemaking in the sinoatrial node.⁴ At this time, pacemaking was primarily thought to be result of the decay of delayed rectifier K⁺ current (K⁺ current decay hypothesis) together with the activation of various inward currents (funny current and T- and L-type Ca²⁺ currents) and facilitated by an elusive inward background current and the lack of inward rectifier K⁺ current.⁴ At the same time, it was known that in Ca²⁺-overloaded Purkinje fibers or ventricular muscle, spontaneous Ca²⁺ release could occur from the sarcoplasmic reticulum (SR). By activating inward Na⁺-Ca²⁺ exchange current, this could produce "TDs" or transient depolarizations, which in turn could result in abnormal pacemaker activity; this abnormal pacemaker activity (resulting from an "internal oscillator") was thought to be distinct from sinoatrial node pacemaker activity (resulting from a "surface membrane oscillator").⁵ Ju and Allen were among the first to raise the possibility that SR Ca²⁺ release together with Na⁺-Ca²⁺ exchange could be involved in normal pacemaking in the heart.⁶ Ju and Allen worked on the sinus venosus of the toad,⁶ while Terrar and Lakatta and colleagues extended the concept to the mammalian sinoatrial node.^7,8 Although all investigators agree that intracellular Ca²⁺ is involved in pacemaking, there is controversy concerning the degree of its importance.⁹ Our view is that many factors are involved in pacemaking, for example rapid and slow delayed rectifier K⁺ currents, funny current, cardiac and neuronal-type Na⁺ currents, T and L-type Ca²⁺ currents, as well as inward Na⁺-Ca²⁺ exchange current (regulated by intracellular Ca²⁺).¹⁰ Now Ju and Allen and colleagues have introduced another factor that is possibly involved in pacemaking: store-operated Ca²⁺ channels (SOCCs).³

SOCCs are Ca²⁺ permeable channels; they are voltage-independent and, therefore, distinct from the voltage-dependent Ca²⁺ channels (Ca_v channels).¹¹ SOCCs are activated by the emptying of intracellular Ca²⁺ stores, and the subsequent Ca²⁺ influx via the SOCCs results in a refilling of the stores.¹¹ SOCCs are well known to be important Ca²⁺ influx pathways in nonexcitable cells, and there is accumulating evidence that they exist in excitable cells, including cardiac ventricular myocytes.^11–13 Despite intense research, the nature of the Ca²⁺ sensor in the Ca²⁺ stores and the signal between the sensor and the SOCCs is unknown.¹¹ The identity of SOCCs is still debated, but TRPCs are likely contenders.¹¹ The TRP (transient receptor potential) channel was first identified in Drosophila, in which it is involved in phototransduction.¹¹ There are seven TRPC family members (TRPC1–7) in mammals, and there is evidence (some of which is controversial and disputed) that 6 of the TRPC channels are SOCCs (the exception is TRPC6).¹¹

Ju et al³ report evidence (from RT-PCR) of transcripts for 6 of the 7 TRPC channels (the exception is TRPC5) in the sinoatrial node. Using immunocytochemistry, they show evidence of some of the TRPC channels at the protein level in sinoatrial node cells: TRPC1, TRPC3, TRPC4, and TRPC6. In particular, Ju et al³ show evidence of TRPC3 and TRPC4 proteins in the sarcolemma of sinoatrial node cells. Most impressively, Ju et al³ show functional evidence of SOCCs in the sinoatrial node: they show that, after store (ie, SR) depletion by removal of extracellular Ca²⁺, the restoration of extracellular Ca²⁺ results in a seemingly massive rise in intracellular Ca²⁺. The rise is most likely the result of Ca²⁺ influx—it is greatly increased by blocking SR Ca²⁺ uptake by cyclopiazonic acid. Blocking L-type Ca²⁺ channels (by nifedipine) or the Na⁺-Ca²⁺ exchanger (by KBR7943) has little or no effect on the Ca²⁺ influx signal, whereas it is greatly reduced by the SOCC blockers (admittedly, not specific), Gd³⁺ and SKF96365. Ju et al³ suggest that SOCCs, as well as being involved in Ca²⁺ handling in the sinoatrial node, may carry a significant inward current, because when they applied the SOCC blocker, SKF96365, pacemaking was significantly slowed. Furthermore, they suggest that there may be a complex interaction between SOCCs, the SR, and Na⁺-Ca²⁺ exchange. For example, cyclopiazonic acid is expected to cause a decrease in the SR Ca²⁺ content and, therefore, a decrease in SR Ca²⁺ release and, therefore, a decrease in inward Na⁺-Ca²⁺ exchange current. This is expected to slow pacemaking. However, the decrease in SR Ca²⁺ content is expected to increase inward SOCC current, and this will oppose any slowing of pacemaking as a result of the decrease in inward Na⁺-Ca²⁺ exchange current.

It is possible that SOCCs are more important in the sinoatrial node than in the working myocardium—whereas Ju et al³ measured substantial SOCC-mediated Ca²⁺ influx in all sinoatrial node preparations, Nakayama et al¹³ only observed a "very subtle" SOCC-mediated Ca²⁺ influx (measured using a comparable protocol) in 25% of mouse, presumably ventricular, myocytes. If SOCCs are more important in the sinoatrial node, this would be a difference in Ca²⁺ handling between the sinoatrial node and the working myocardium. Such a difference would not be a surprise, because Ca²⁺ handling in the sinoatrial node and the working myocardium has been shown to be different in many other respects (Figure). As compared with working myocardial cells, cells from the center of the sinoatrial node:

View larger version (41K): [in this window] [in a new window]   Ca2+ handling in the sinoatrial node. A, Immunolabeling of RYR2 in atrial (left) and sinoatrial (right) cells from the rabbit. In the atrial cell, there is subsarcolemmal labeling (corresponding to subsarcolemmal SR) as well as intracellular striated labeling (corresponding to corbular SR; N.B., there are no t tubules in atrial cells). Adapted from Musa et al.14 In the sinoatrial node cells, there is only subsarcolemmal labeling. B, Cartoon of Ca2+ handling in a sinoatrial node cell.

(1) are small and, therefore, their surface area:volume ratio is high—sarcolemmal fluxes of Ca²⁺ may, therefore, be more influential (Figure, A);

(2) lack t tubules;

(3) only have subsarcolemmal SR—for example, they lack the corbular SR characteristic of atrial cells (Figure, A)¹⁴;

(4) express the L-type Ca²⁺ channel isoform, Ca_v1.3, as well as or instead of Ca_v1.2¹⁵;

(5) possibly have a lower expression of SERCA2a (SR Ca²⁺ pump), RYR2 (SR Ca²⁺ release channel), and NCX1 (Na⁺-Ca²⁺ exchanger)^14,15;

(6) express RYR3 as well as RYR2¹⁵;

(7) possibly have a higher diastolic intracellular Ca²⁺ concentration and smaller intracellular Ca²⁺ transient¹⁶; and

(8) have a high intracellular cAMP concentration resulting in oscillatory Ca²⁺ release from the SR (to facilitate pacemaking).¹⁷

In conclusion, Ju et al³ have introduced a new family of channels, the TRPCs, which may play a role in both Ca²⁺ handling and pacemaking in the sinoatrial node. Of course much remains to be done. Perhaps the most urgent task is to measure SOCC current and function in single sinoatrial node cells. So far, familial (ie, hereditary) sick sinus syndrome (sinoatrial node dysfunction) in patients has been linked to mutations in HCN4 and Na_v1.5.¹⁰ If SOCCs and other Ca²⁺ handling proteins are important in pacemaking, it is possible that these too will be linked to familial sick sinus syndrome.

	Acknowledgments

 
Sources of Funding

M.R.B. and H.D. are supported by the British Heart Foundation (RG/06/005).

Disclosures

None.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

Top References

 

1. Keith A. An Autobiography. Sir Arthur Keith. London: Watts & Co.; 1950.
2. Keith A, Flack MW. The form and nature of the muscular connections between the primary divisions of the vertebrate heart. Journal of Anatomy and Physiology. 1907; 41: 172–189.
3. Ju Y-K, Chu Y, Chaulet H, Lai D, Gervasio OL, Graham RM, Cannell MB, Allen DG Store-operated Ca²⁺ influx and expression of the TRPC genes in mouse sinoatrial node. Circ Res. 2007; 100: 1605–1614.
4. Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sino-atrial node. Physiol Rev. 1993; 73: 197–227.[Free Full Text]
5. Tsien RW, Kass RS, Weingart R. Cellular and subcellular mechanisms of cardiac pacemaker oscillations. J Exp Biol. 1979; 81: 205–215.[Abstract/Free Full Text]
6. Ju Y-K, Allen DG. Intracellular calcium and Na²⁺-Ca²⁺ exchange current in isolated toad pacemaker cells. J Physiol. 1998; 508: 153–166.[Abstract/Free Full Text]
7. Rigg L, Terrar DA. Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sino-atrial node. Exp Physiol. 1996; 81: 877–880.[Abstract]
8. Bogdanov KY, Vinogradova TM, Lakatta EG. Sinoatrial nodal cell ryanodine receptor and Na⁺-Ca²⁺ exchanger: molecular partners in pacemaker regulation. Circ Res. 2001; 88: 1254–1258.[Abstract/Free Full Text]
9. Honjo H, Inada S, Lancaster MK, Yamamoto M, Niwa R, Jones SA, Shibata N, Mitsui K, Horiuchi T, Kamiya K, Kodama I, Boyett MR. Sarcoplasmic reticulum Ca²⁺ release is not a dominating factor in sinoatrial node pacemaker activity. Circ Res. 2003; 92: e41–e44.[Medline] [Order article via Infotrieve]
10. Dobrzynski H, Boyett MR, Anderson RH. New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation. 2007; 115: 1921–1932.[Free Full Text]
11. Parekh AB, Putney JW Jr. Store-operated calcium channels. Physiol Rev. 2005; 85: 757–810.[Abstract/Free Full Text]
12. Seth M, Sumbilla C, Mullen SP, Lewis D, Klein MG, Hussain A, Soboloff J, Gill DL, Inesi G. Sarco(endo)plasmic reticulum Ca²⁺ ATPase (SERCA) gene silencing and remodeling of the Ca²⁺ signaling mechanism in cardiac myocytes. Proc Natl Acad Sci U S A. 2004; 101: 16683–16688.[Abstract/Free Full Text]
13. Nakayama H, Wilkin BJ, Bodi I, Molkentin JD. Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J. 2006; 20: 1660–1670.[Abstract/Free Full Text]
14. Musa H, Lei M, Honjo H, Jones SA, Dobrzynski H, Lancaster MK, Takagishi Y, Henderson Z, Kodama I, Boyett MR. Heterogeneous expression of Ca²⁺ handling proteins in sinoatrial node. J Histochem Cytochem. 2002; 50: 311–324.[Abstract/Free Full Text]
15. Tellez JO, Dobrzynski H, Greener ID, Graham GM, Laing E, Honjo H, Hubbard SJ, Boyett MR, Billeter R. Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit. Circ Res. 2006; 99: 1384–1393.[Abstract/Free Full Text]
16. Lancaster MK, Jones SA, Harrison SM, Boyett MR. Intracellular Ca²⁺ and pacemaking within the rabbit sinoatrial node: heterogeneity of role and control. J Physiol. 2004; 556: 481–494.[Abstract/Free Full Text]
17. Vinogradova TM, Lyashkov AE, Zhu W, Ruknudin AM, Sirenko S, Yang D, Deo S, Barlow M, Johnson S, Caffrey JL, Zhou YY, Xiao RP, Cheng H, Stern MD, Maltsev VA, Lakatta EG. High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca²⁺ store oscillations and spontaneous beating of cardiac pacemaker cells. Circ Res. 2006; 98: 505–514.[Abstract/Free Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Boyett, M.R. Articles by Dobrzynski, H. Search for Related Content PubMed PubMed Citation Articles by Boyett, M.R. Articles by Dobrzynski, H.