Biomedical Engineering Reference
In-Depth Information
O
O
O
O
K
+
Na
+
A
O
O
O
O
Ion
ilter
B
A
O
O
O
O
Na
+
K
+
O
O
O
O
(A)
Gate
(B)
FIGURE 13.4
(A) Potassium channel structure with selectivity i lter at the outer pore and gating mechanism
at the inner pore. (B) Selectivity mechanism. The distance between the K
+
ions and the oxygen atoms is the
same in water as in the selectivity i lter enabling the K
+
ions to enter the pore at no energy cost. This is differ-
ent for Na
+
ions, so they are excluded from the pore. (From Alberts, B. et al.,
Molecular Biology of the Cell
,
2002 Garland Publishing Inc. and Doyle, D.A. et al.
Science
280: 69-77, 1998.)
the pore is unchanged. By this means high selectivity and high permeability of the ions passing in
single i le is obtained. Although Na
+
ions are smaller than K
+
ions they will not enter the pore since
it is energetically unfavorable.
13.2 PHYSIOLOGY AND PHARMACOLOGY OF VOLTAGE-GATED
ION CHANNELS—POTASSIUM CHANNELS
The 2-TM K
ir
channel family gives rise to six subtypes, which play diverse roles in the body. Many
K
ir
channels are open at resting membrane potential and clamp the potential at −70 and −90 mV in
nerve and heart cells, respectively (e.g., K
ir
4 and K
ir
2). The K
ir
3 channels are gated by binding of
the
-subunit from the G
i
-protein. This mechanism is important in the atria of the heart, where
stimulation of the para-sympathetic vagus nerve leads to release of acetylcholine, activating the G
i
protein and subsequently the K
ir
3 channel to hyperpolarize the pacemaker cells.
The K
ir
6 channels are expressed both in heart, vasculature, nerve, and in the pancreatic
βγ
-cells.
This channel subtype can only be expressed in cells when it coassembles with its accessory
subunit, the so-called sulfonyl urea receptors (SUR) of the ABC transporter family. The
β
-cell
subtype is composed of 4 K
ir
6.2 + 4 SUR1. Like other K
ir
channels it is activated by binding of
phosphatidylinositol-4, 5-bisphosphate (PIP
2
). In contrast the complex is blocked by ATP bind-
ing to the internal surface of K
ir
6.2 and activated by MgADP binding to the nucleotide-binding
domains of SUR1. The channel complex is also denoted as the K
ATP
channel and it is interesting
for two reasons: it is a key regulatory protein in the
β
-cells coupling plasma glucose levels to
insulin secretion, and the SUR has a well-exploited high-afi nity drug-binding site.
Briel y, insulin secretion is regulated by the following mechanism: an increase in plasma glu-
cose leads, through an increased ATP level in the
β
-cells, to block the K
ATP
channel, depolariza-
tion, Ca
2+
-inl ux, and insulin secretion (Figure 13.5). If this regulation is dysfunctional as in many
type-2 diabetic patients, a similar functional effect can be obtained by directly blocking the K
ATP
channel pharmacologically. The drug-binding site on SUR1 is on the inside of TM15 (plus partly
on the inside of TM14), and the bulky substitution mutation S1237Y disrupts the site. Tolbutamide
β
