**4. ATP-sensitive potassium channel in the vascular system**

Functional KATP channels are hetero-octameric membrane protein complexes that comprise four inward-rectifier potassium channel 6 (Kir6, either Kir6.1 or Kir6.2) subunits and four ABCC (ATP-binding cassette, subfamily C) family member sulfonylurea receptor (SUR) subunits, including SUR1, SUR2A, or SUR2B. The Kir6 subunit (Kir6.1 or Kir6.2) has two membrane-spanning regions (M1 and M2) with intracellular N- and C-termini. The latter two are alternative splice variants, differing from each other only in the C-terminal 42 amino acids. The SURx subunit has 17 transmembrane regions, arranged in three domains: TMD0, TMD1, and TMD2. A conserved intracellular nucleotide binding fold (NBF1), with Walker A and Walker B domains, exists between TMD1 and TMD2. A second intracellular nucleotide binding fold (NBF2) exists in the C-terminus region of the protein. It is thought that NBF1 binds (and hydrolyzes) MgATP, whereas MgADP binds primarily to NBF2 to stimulate channel activity (**Figure 3**). KATP channels are expressed in a variety of cell types, including cardiac, smooth, and skeletal muscles, with tissue-specific diversity in the receptor subtypes. While pancreatic KATP channels are associated with SUR1, cardiovascular channels interact with SUR2 subtypes. In VSMC, SUR2B interacts with Kir6.1 to form KATP, and more rarely, Kir6.2 may be the ion pore-forming subunit. The Kir6 channel pore-forming subunits are the ATP sensor, and their activity is regulated by PIP2. KATP channels are inhibited by elevated intracellular ATP and stimulated by ADP under physiological conditions [46, 65–67].

In blood vessels, KATP channels remain closed under normal physiological conditions; however, they are activated when the cell metabolism is disturbed by hypoxia or ischemia, resulting in an efflux of potassium ions and membrane hyperpolarization. The decreased membrane excitability leads to a shortened cardiac action potential, inhibition of neurotransmitter release, and relaxation of vascular smooth muscles, which play key roles in limiting cellular damage or regulating blood pressure [68, 69]. In skeletal muscle arteries and arteries, alterations in metabolic activity induce changes in local oxygen tension and are an important mediator of

#### **Figure 3.**

*KATP channels are hetero-octameric membrane protein complexes that are composed of four inward-rectifier potassium channel 6 (Kir6.x) subunits and sulfonylurea receptor (SURx) subunits. The Kir6.x subunit (Kir6.1 or Kir6.2) has two membrane-spanning regions (M1 and M2) with intracellular N- and C-termini. Two SURx subunits have been described: SUR1 and SUR2 (SUR2A or SUR2B). The latter two are alternative splice variants, differing from each other only in the C-terminal 42 amino acids. The SURx subunit has 17 transmembrane regions, arranged in three domains: TMD0, TMD1, and TMD2. A conserved intracellular nucleotide binding fold (NBF1), with Walker A and Walker B domains, exists between TMD1 and TMD2. A second intracellular nucleotide binding fold (NBF2) exists in the C-terminus region of the protein. It is thought that NBF1 binds (and hydrolyzes) MgATP, whereas MgADP binds primarily to NBF2 to stimulate channel activity.*

**35**

*Potassium Channels in the Vascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.82474*

vasomotor responses. Vasodilation (hypoxic vasodilation) is caused by decreased oxygen tension, and vasoconstriction (hyperoxic vasoconstriction) is caused by the increased oxygen tension [70, 71]. KATP channels are known to link cell metabolism and cell membrane potential, and decreased oxygen tension results in a depletion of intracellular ATP levels, which contributes to the opening of KATP channels and the

Renal hyperfiltration is a main characteristic of the early stage of type 1 diabetes mellitus (DM), and altered renal hemodynamics promote the eventual development of diabetic nephropathy. The hyperfiltration state is ascribed to the dilation of afferent arterioles and diminished responsiveness of this vascular segment to various vasoconstrictors, while the diameters of efferent arterioles and vasoconstrictor responsiveness are typically unaltered [72–74]. The membrane potential (Em) and afferent arteriolar dilation are closely related in subjects with DM. KATP channels are quiescent in normal rats but exert a vasodilatory effect on afferent arteriolar tone during the hyperfiltration stage of diabetes. Increases in both the functional availability and basal activation of KATP channels promote afferent arteriolar vasodilation during the early stage of DM, changes that likely contribute to the etiology of diabetic hyperfiltration [73]. However, the involvement of KATP channels in the renal afferent arteriolar dilation during the early stage of DM is still controversial. Additional studies are needed to completely elucidate the potential roles of renal

KV channels comprise a large family of channels that are expressed in both excitable and nonexcitable cells. In excitable cells, such as neurons or cardiac myocytes, the control of the resting membrane potential (resting Em) and frequency and duration of action potentials depend on KV channels. In nonexcitable tissues, these channels are involved in various processes ranging from secretion to cell proliferation [75]. In humans, KV channels are encoded by 40 genes, and each Kv channel gene encodes a single protein; functional Kv channels are divided into 12 subfamilies (KV1–KV12). All mammalian KV channels consist of four α-subunits and six transmembrane α-helical segments (S1–S6), and a membrane-reentering P-loop forms each α-subunit. This ion conduction pore is lined by four S5–P–S6 sequences. The four S1–S4 segments, each containing four positively charged arginine residues in the S4 helix, act as voltage sensor domains and "gate" the pore by "pulling" on the S4–S5 linker [76, 77]. The large number of KV channel genes combined with the possibility of heterotetramerization creates a large functional diversity of KV currents. This diversity is increased by the interactions of these channels with accessory proteins that are capable of modulating the gating properties and assist in trafficking and multimerization [75]. Since the KV channel subunits form homo and heterotetramers, the biophysical properties, physiological regulatory mechanisms, and pharmacological properties of these channels vary. Although the KV1.1–1.6 mRNAs have been detected in rat cerebral arteries, only the KV1.2 and 1.5 proteins were detected, suggesting that in the cerebral vasculature, the functional KV channel is a KV1.2/1.5 heterotetramer. Members of the KV1 and KV2 family are postulated to be the predominant Kv channels that regulate arterial tone (**Table 1**) [78, 79]. KV channels regulate membrane potential. Numerous studies have been conducted to explore the mechanisms by which these channels affect vascular tone in subjects with hypertension. Under Ca2+-replete conditions, KV currents in arterial SMCs from hypertensive animals are altered. KV1.2 is expressed at higher levels, whereas KV1.5 is expressed at the same levels in SMCs from hypertensive animals

subsequent hyperpolarization and relaxation of the VSMCs [71].

vascular KATP channels in early diabetic hyperfiltration [74].

**5. KV channel in VSMCs**

#### *Potassium Channels in the Vascular Diseases DOI: http://dx.doi.org/10.5772/intechopen.82474*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

ADP under physiological conditions [46, 65–67].

**4. ATP-sensitive potassium channel in the vascular system**

Functional KATP channels are hetero-octameric membrane protein complexes that comprise four inward-rectifier potassium channel 6 (Kir6, either Kir6.1 or Kir6.2) subunits and four ABCC (ATP-binding cassette, subfamily C) family member sulfonylurea receptor (SUR) subunits, including SUR1, SUR2A, or SUR2B. The Kir6 subunit (Kir6.1 or Kir6.2) has two membrane-spanning regions (M1 and M2) with intracellular N- and C-termini. The latter two are alternative splice variants, differing from each other only in the C-terminal 42 amino acids. The SURx subunit has 17 transmembrane regions, arranged in three domains: TMD0, TMD1, and TMD2. A conserved intracellular nucleotide binding fold (NBF1), with Walker A and Walker B domains, exists between TMD1 and TMD2. A second intracellular nucleotide binding fold (NBF2) exists in the C-terminus region of the protein. It is thought that NBF1 binds (and hydrolyzes) MgATP, whereas MgADP binds primarily to NBF2 to stimulate channel activity (**Figure 3**). KATP channels are expressed in a variety of cell types, including cardiac, smooth, and skeletal muscles, with tissue-specific diversity in the receptor subtypes. While pancreatic KATP channels are associated with SUR1, cardiovascular channels interact with SUR2 subtypes. In VSMC, SUR2B interacts with Kir6.1 to form KATP, and more rarely, Kir6.2 may be the ion pore-forming subunit. The Kir6 channel pore-forming subunits are the ATP sensor, and their activity is regulated by PIP2. KATP channels are inhibited by elevated intracellular ATP and stimulated by

In blood vessels, KATP channels remain closed under normal physiological conditions; however, they are activated when the cell metabolism is disturbed by hypoxia or ischemia, resulting in an efflux of potassium ions and membrane hyperpolarization. The decreased membrane excitability leads to a shortened cardiac action potential, inhibition of neurotransmitter release, and relaxation of vascular smooth muscles, which play key roles in limiting cellular damage or regulating blood pressure [68, 69]. In skeletal muscle arteries and arteries, alterations in metabolic activity induce changes in local oxygen tension and are an important mediator of

*KATP channels are hetero-octameric membrane protein complexes that are composed of four inward-rectifier potassium channel 6 (Kir6.x) subunits and sulfonylurea receptor (SURx) subunits. The Kir6.x subunit (Kir6.1 or Kir6.2) has two membrane-spanning regions (M1 and M2) with intracellular N- and C-termini. Two SURx subunits have been described: SUR1 and SUR2 (SUR2A or SUR2B). The latter two are alternative splice variants, differing from each other only in the C-terminal 42 amino acids. The SURx subunit has 17 transmembrane regions, arranged in three domains: TMD0, TMD1, and TMD2. A conserved intracellular nucleotide binding fold (NBF1), with Walker A and Walker B domains, exists between TMD1 and TMD2. A second intracellular nucleotide binding fold (NBF2) exists in the C-terminus region of the protein. It is thought that NBF1 binds (and* 

*hydrolyzes) MgATP, whereas MgADP binds primarily to NBF2 to stimulate channel activity.*

**34**

**Figure 3.**

vasomotor responses. Vasodilation (hypoxic vasodilation) is caused by decreased oxygen tension, and vasoconstriction (hyperoxic vasoconstriction) is caused by the increased oxygen tension [70, 71]. KATP channels are known to link cell metabolism and cell membrane potential, and decreased oxygen tension results in a depletion of intracellular ATP levels, which contributes to the opening of KATP channels and the subsequent hyperpolarization and relaxation of the VSMCs [71].

Renal hyperfiltration is a main characteristic of the early stage of type 1 diabetes mellitus (DM), and altered renal hemodynamics promote the eventual development of diabetic nephropathy. The hyperfiltration state is ascribed to the dilation of afferent arterioles and diminished responsiveness of this vascular segment to various vasoconstrictors, while the diameters of efferent arterioles and vasoconstrictor responsiveness are typically unaltered [72–74]. The membrane potential (Em) and afferent arteriolar dilation are closely related in subjects with DM. KATP channels are quiescent in normal rats but exert a vasodilatory effect on afferent arteriolar tone during the hyperfiltration stage of diabetes. Increases in both the functional availability and basal activation of KATP channels promote afferent arteriolar vasodilation during the early stage of DM, changes that likely contribute to the etiology of diabetic hyperfiltration [73]. However, the involvement of KATP channels in the renal afferent arteriolar dilation during the early stage of DM is still controversial. Additional studies are needed to completely elucidate the potential roles of renal vascular KATP channels in early diabetic hyperfiltration [74].
