Calcium- and sodium-activated potassium channels (K<sub>Ca</sub>, K<sub>Na</sub>) | Introduction

Home
Targets
Ion channels
Calcium- and sodium-activated potassium channels (K_Ca, K_Na)
Introduction

Calcium- and sodium-activated potassium channels (K_Ca, K_Na): Introduction

Adapted from the original 2005 article in Pharmacological Reviews [17], and update published in 2017 [7].

The second major group of six/seven transmembrane potassium-selective channels consists of the K_Ca channels (for reviews, see [2,9-11,16]), and Table 1 shows the International Union of Pharmacology (IUPHAR) names of the members of this group together with their HUGO Gene Nomenclature Committee (HGNC) designations and other commonly used names. The phylogenetic trees in Fig. 1 illustrate the fact that these channels form two well defined but only distantly related groups.

TABLE 1 - K_Ca channels: IUPHAR names of the members of the K_Ca group of potassium channels are shown, together with their HGNC designations and other commonly used names. BK, big-conductance K⁺ channel; SK, small-conductance K⁺ channel; IK, intermediate-conductance K⁺ channel.


IUPHAR	HGNC	Other
K_Ca1.1	KCNMA1	Slo, Slo1, BK
K_Ca2.1	KCNN1	SK_Ca1
K_Ca2.2	KCNN2	SK_Ca2
K_Ca2.3	KCNN3	SK_Ca3
K_Ca3.1	KCNN4	IK_Ca1
K_Ca4.1	KCNT1	Slack, Slo2.2
K_Ca4.2	KCNT2	Slick, Slo2.1
K_Ca5.1	KCNU1	Slo3

One of these groups (Fig. 1A) includes the three "small-conductance" K_Ca channels (K_Ca2.1, 2.2, and 2.3) [8] and the "intermediate-conductance" channel K_Ca3.1 [5-6]. These channels are voltage-insensitive and are activated by low concentrations of internal Ca²⁺ (<1.0 μM), in contrast to K_Ca1.1 (KCNMA1, Slo1), which is activated by both voltage and internal Ca²⁺. The three small-conductance K_Ca channels are sensitive to block by apamin (100 pM-10 nM), which distinguishes them from all other K_Ca channels. Both small- and intermediate-conductance K_Ca channels play important roles in many processes involving Ca²⁺-dependent signaling in both electrically excitable and nonexcitable cells. They do not bind Ca²⁺ directly but rather detect Ca²⁺ by virtue of calmodulin, which is constitutively bound to the C-terminal region [4,19]. Binding of calcium to this calmodulin results in conformational changes that are in turn responsible for channel gating [14].

FIG. 1. Phylogenetic tree for K_Ca channels. A, K_Ca2/3 group. B, K_Ca1/4/5 group. Amino acid sequence alignments for the known members of the human K_Ca family were created using CLUSTALW. Analysis by maximum parsimony using PAUP* resulted in the above tree. International Union of Pharmacology and HUGO Gene Nomenclature Committee names of the genes are shown together with their chromosomal location.

The tree shown in Fig. 1B illustrates the sequence relationships within the second group of K_Ca channels, which includes K_Ca1.1 (Slo or Slo1), K_Ca4.1 (Slack or Slo2.2), K_Ca4.2 (Slick or Slo2.1), and K_Ca5.1 (Slo3). K_Ca1.1 has been extensively studied in the brain, cochlea, and muscle, and alternate splicing of its mRNA is known to produce considerable functional diversity [3,18]. Unlike the K_Ca2 and K_Ca3 channels, binding of calcium by K_Ca1.1 is not dependent on its association with calmodulin but is thought to be mediated by at least three divalent cation binding sites in the cytoplasmic carboxyl domain of each channel subunit. Two independent high-affinity Ca²⁺ binding sites are formed by a negatively charged segment in the distal carboxyl terminal portion, termed the "calcium bowl" [12] and within the first RCK domain encoded by the proximal C-terminal portion [1,20]. A third low-affinity divalent cation binding site is also found in the first RCK domain [15], which contributes to activation by Mg²⁺ and Ca²⁺ at high concentrations (>1 mM).

The three other members of this group, K_Ca4.1, 4.2, and 5.2 [6,13,21], were all included in the K_Ca nomenclature since they all are clearly members of this structurally related group of genes. However, much more is now known about the functional properties of the members of this gene family than was known when these names were assigned several years ago, and this presents a possible conundrum for a nomenclature based on functional rather than structural similarity. Unlike the founding member K_Ca1.1, which is in fact activated by internal Ca²⁺, none of the other members of this group seems to be similarly Ca²⁺-activated. In fact, for the most part, these three are insensitive to internal Ca²⁺. K_Ca4.2 and K_Ca4.1 are activated by internal Na⁺ and Cl^- [21], and K_Ca5.1 is activated by internal alkalization (OH^-) [13]. Therefore, although they are structurally related to K_Ca1.1, these three channels cannot correctly be described as "calcium-activated" channels based on functional criteria. This may be a subject for discussion among researchers in this field and those bodies responsible for standardizing gene nomenclature.

References

Show »« Hide

1. Bao L, Rapin AM, Holmstrand EC, Cox DH. (2002) Elimination of the BK(Ca) channel's high-affinity Ca(2+) sensitivity. J Gen Physiol, 120 (2): 173-89. [PMID:12149279]

2. Cox DH. (2005) The BKCa channel's Ca2+-binding sites, multiple sites, multiple ions. J Gen Physiol, 125 (3): 253-5. [PMID:15738047]

3. Faber ES, Sah P. (2003) Calcium-activated potassium channels: multiple contributions to neuronal function. Neuroscientist, 9 (3): 181-94. [PMID:15065814]

4. Fanger CM, Ghanshani S, Logsdon NJ, Rauer H, Kalman K, Zhou J, Beckingham K, Chandy KG, Cahalan MD, Aiyar J. (1999) Calmodulin mediates calcium-dependent activation of the intermediate conductance KCa channel, IKCa1. J Biol Chem, 274 (9): 5746-54. [PMID:10026195]

5. Ishii TM, Silvia C, Hirschberg B, Bond CT, Adelman JP, Maylie J. (1997) A human intermediate conductance calcium-activated potassium channel. Proc Natl Acad Sci USA, 94 (21): 11651-6. [PMID:9326665]

6. Joiner WJ, Wang LY, Tang MD, Kaczmarek LK. (1997) hSK4, a member of a novel subfamily of calcium-activated potassium channels. Proc Natl Acad Sci USA, 94 (20): 11013-8. [PMID:9380751]

7. Kaczmarek LK, Aldrich RW, Chandy KG, Grissmer S, Wei AD, Wulff H. (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium-Activated and Sodium-Activated Potassium Channels. Pharmacol Rev, 69 (1): 1-11. [PMID:28267675]

8. Kohler M, Hirschberg B, Bond CT, Kinzie JM, Marrion NV, Maylie J, Adelman JP. (1996) Small-conductance, calcium-activated potassium channels from mammalian brain. Science, 273 (5282): 1709-14. [PMID:8781233]

9. Lingle CJ. (2002) Setting the stage for molecular dissection of the regulatory components of BK channels. J Gen Physiol, 120 (3): 261-5. [PMID:12198086]

10. Magleby KL. (2003) Gating mechanism of BK (Slo1) channels: so near, yet so far. J Gen Physiol, 121 (2): 81-96. [PMID:12566537]

11. Moczydlowski EG. (2004) BK channel news: full coverage on the calcium bowl. J Gen Physiol, 123 (5): 471-3. [PMID:15111642]

12. Schreiber M, Salkoff L. (1997) A novel calcium-sensing domain in the BK channel. Biophys J, 73 (3): 1355-63. [PMID:9284303]

13. Schreiber M, Wei A, Yuan A, Gaut J, Saito M, Salkoff L. (1998) Slo3, a novel pH-sensitive K+ channel from mammalian spermatocytes. J Biol Chem, 273 (6): 3509-16. [PMID:9452476]

14. Schumacher MA, Rivard AF, Bächinger HP, Adelman JP. (2001) Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin. Nature, 410 (6832): 1120-4. [PMID:11323678]

15. Shi J, Krishnamoorthy G, Yang Y, Hu L, Chaturvedi N, Harilal D, Qin J, Cui J. (2002) Mechanism of magnesium activation of calcium-activated potassium channels. Nature, 418 (6900): 876-80. [PMID:12192410]

16. Stocker M. (2004) Ca(2+)-activated K+ channels: molecular determinants and function of the SK family. Nat Rev Neurosci, 5 (10): 758-70. [PMID:15378036]

17. Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H. (2005) International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol Rev, 57 (4): 463-72. [PMID:16382103]

18. Weiger TM, Hermann A, Levitan IB. (2002) Modulation of calcium-activated potassium channels. J Comp Physiol A Neuroethol Sens Neural Behav Physiol, 188 (2): 79-87. [PMID:11919690]

19. Xia XM, Fakler B, Rivard A, Wayman G, Johnson-Pais T, Keen JE, Ishii T, Hirschberg B, Bond CT, Lutsenko S et al.. (1998) Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature, 395 (6701): 503-7. [PMID:9774106]

20. Xia XM, Zeng X, Lingle CJ. (2002) Multiple regulatory sites in large-conductance calcium-activated potassium channels. Nature, 418 (6900): 880-4. [PMID:12192411]

21. Yuan A, Santi CM, Wei A, Wang ZW, Pollak K, Nonet M, Kaczmarek L, Crowder CM, Salkoff L. (2003) The sodium-activated potassium channel is encoded by a member of the Slo gene family. Neuron, 37 (5): 765-73. [PMID:12628167]